Immediate Release Abuse-Deterrent Granulated Dosage Forms

ABSTRACT

Described are oral dosage forms that contain abuse-deterrent features and that contain core-shell polymers that include an active pharmaceutical ingredient, with particular examples including immediate release dosage forms that contain a drug that is commonly susceptible to abuse.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/898,207, filed Oct. 31, 2013, the disclosure of which is incorporatedherein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to the field of oral dosage forms thatcontain abuse-deterrent features, in particular including immediaterelease dosage forms that contain a drug that is commonly susceptible toabuse.

BACKGROUND

Pharmaceutical products, including both prescription andover-the-counter pharmaceutical products, while useful for improvinghealth of a person in need, are also susceptible to intentional andunintentional abuse and overdosing. Examples of commonly abused activepharmaceutical ingredients include psychoactive drugs, anxiolytics,sedative hypnotics, stimulants, depressants, and analgesics such asnarcotic analgesics, among others. A complete list of specific drugcompounds that are commonly abused would be lengthy; a short listing ofsome classes of drugs commonly abused includes opioids and morphinederivatives, barbiturates, amphetamines, ketamine, and other drugs thatcan cause psychological or physical dependence.

Some common techniques for intentionally abusing a drug begin with anabuser obtaining a solid dosage form such as an orally administeredtablet or capsule, and crushing the solid dosage form into a powder. Thepowder may be administered by an abuser by nasal insufflation (i.e.,“snorting”) to introduce the drug to the abuser's bloodstreamintranasally. Alternately, the crushed dosage form may be combined witha solvent that is capable of dissolving the drug (active pharmaceuticalingredient, or “API”), and the solvent with the dissolved drug may beinjected directly into an abuser's bloodstream.

Alternatively, with immediate release oral dosage forms, an abuser mightsimply ingest multiple units (e.g., tablets) of the dosage formtogether, e.g., simultaneously. Each one of the multiple dosage formunits—immediately releases an amount of drug to produce a short-termconcentration spike of the drug in the user's bloodstream and a desired“high” in the user.

The pharmaceutical industry has identified various mechanisms ofadapting drug compositions and oral dosage forms that can be useful todiscourage abuse of oral dosage forms. Pharmaceutical companies havestudied dosage forms that contain a nasal irritant or an effervescentagent, which can cause irritation or pain in a nasal passage if thedosage form is crushed and then snorted, thus discouraging abuse bynasal insufflation. Pharmaceutical companies studied adding gellingpolymers to dosage forms to prevent abuse by injection. If the dosageform is crushed to a powder and combined with a small amount of solvent,the gelling polymer can cause the combination to take the form of ahighly viscous liquid or gel that cannot be administered by injection.Another possible abuse deterrent may be addition of an emetic agentwhich can deter abuse by causing emesis on ingestion of multiple doses.Another abuse deterrent involves adding an antagonist of an API to adosage form that will substantially block the effect of the drug.

Although the pharmaceutical industry has identified of a variety ofabuse deterrent features useful with oral dosage forms, there iscontinuing need to improve and identify new abuse deterrent features toinhibit or prevent abuse or overdosing of active pharmaceuticalingredients.

SUMMARY

The following description relates to oral dosage forms that are usefulfor immediate release of an active pharmaceutical ingredient or “API.”

The dosage form can be designed to release the API as desired in animmediate release dosage form, and can also include one or a combinationof feature that will prevent or deter abuse of the API. The abusedeterrent features described herein can be included singly or in anycombination in an immediate release dosage form.

As a first type of abuse deterrent feature, a dosage form as describedcan include a gelling polymer to prevent or compromise abuse practiceswherein the dosage form is crushed and then combined with a small amountof a solvent to produce a liquid composition that contains aconcentrated amount of API and that can be delivered to an abuser usinga syringe. The gelling polymer can be any polymer useful to achieve thisfunctionality, and can be placed in the dosage form at any location toallow the gelling polymer to perform as described and still allowimmediate release of the API. A gelling polymer can be included in acore of a coated of core-shell particle or in a matrix of a dosage formthat suspends the core-shell particles. The core may contain any amountof gelling polymer, such as from 0 to 100 percent gelling polymer basedon a total weight of the core. Alternately, the core in a core-shellparticle may comprise a filler, e.g., up to 100 percent filler, such asa sugar sphere or microcrystalline cellulose sphere (up to 100 percentmicrocrystalline cellulose spheres such as those available under thetrade name Celphere®).

Another type of abuse deterrent feature can be a wax that alone or withother ingredients, e.g., the gelling polymer, is effective incompromising abuse practices wherein a dosage form is crushed andcombined with a solvent to produce a liquid composition that can beabused by nasal insufflation or delivered to an abuser using a syringe.The wax can additionally inhibit or prevent an abuser from grinding thedosage form into a powder because upon grinding the wax will smear asopposed to fracturing or powdering. Similar to the gelling polymer, waxcan be included in a dosage form at any location that allows the wax tofunction as an abuse deterrent feature while not interfering with animmediate release profile of the API. For example, a wax can be includedin a core of a coated particle. A core may contain any amount of wax,such as from 0 to 100 percent wax based on a total weight of the core,such as up to 50, 75, or 80 weight percent wax based on a total weightof the core.

Still another type of abuse deterrent feature can be a filler or binderthat alone or in combination with other ingredients can compromise abusepractices wherein a dosage form is being crushed and combined with asmall amount of a solvent to produce a liquid composition that can bedelivered to an abuser using a syringe. The filler or binder can inhibitor prevent an abuser from grinding the dosage form into a powder becauseupon grinding, the polymeric filler or binder will smear as opposed tofracturing or powdering. The filler or binder can be included in adosage form in any manner and location that allows the filler or binderto function as an abuse deterrent feature while not interfering with animmediate release profile of the API. For example, a filler or bindercan be included in a core of a coated particle. A core may contain anyamount of polymeric filler or binder such as from 0 to 100 percentfiller or binder on a total weight of the core, or up to 50, 75, or 80weight percent filler or binder based on a total weight of the core.

Yet another type of abuse deterrent feature can be a film layer thatsurrounds or covers API in a dosage form and that is optionallyresistant to being dissolved by one or more of the solvents commonlyused by abusers to dissolve an API for injection, including water andC₁-C₄ alcohols such as ethanol, methanol, and mixtures thereof. The filmlayer may be prepared from any film material that is disposed as acontinuous layer on a coated particle at a location to enclose andsurround the API. Examples of film layers can optionally and preferablyprovide properties of a solvent-resistant film, which is a film that isslow or difficult to dissolve in a limited or small volume of one thesolvents commonly used by abusers to dissolve API of a dosage form. Toaccess an API of a dosage form an abuser may grind the dosage form andcombine the ground dosage form with a solvent (as described) in anattempt to produce a solution that contains the concentrated API and thesolvent, and that may be efficiently injected or snorted. By being slowto dissolve or insoluble in one or more of water, or a C₁-C₄ alcoholsuch as ethanol, methanol, etc., a solvent-resistant film layer thatsurrounds API of a dosage form can prevent an abuser from easilyaccessing and so manipulating the API.

In exemplary embodiments, an immediate release dosage form can includethese features in a coated particle, such as a core-shell particle. Anexemplary core-shell particle can include a core and one or more layerssurrounding the core. For such a core-shell particle, the API may beincluded in the core, or in one or more layers surrounding the core, orin both the core and one or more layers surrounding the core. The corecan include any one or more of: a gelling polymer, wax, binder, orfiller, alone or in combination. Alternately, the core may comprise amicrocrystalline cellulose or sugar sphere.

A film layer may surround and enclose the core, or an API-containinglayer that is disposed around the core. The film layer may preferably bea solvent-resistant film in the form of a continuous coating that coversthe core, which contains API, or that covers an API-containing layer orcoating disposed around the core.

According to other various embodiments, a coated particle as describedherein can be useful in a dosage form that includes one or more optionalabuse deterrent features, and a matrix such as a compressed matrix thatis formed to allow for immediate release of the API present in thecoated particles. An exemplary matrix composition may compriseadditional gelling polymer, disintegrant, or both additional gellingpolymer and disintegrant. The expression “additional gelling polymer” asused above means an amount of gelling polymer that is in addition to anamount of gelling polymer present in the coated particles. Theadditional gelling polymer may be the same or different in nature,chemistry, molecular weight, etc., as compared to the gelling polymerthat is included in the coated particles. A disintegrant as a componentof the matrix may be useful to facilitate release of the API of thedosage form, e.g., API present in the coated particles.

The active pharmaceutical ingredient included in the dosage form,especially in the coated particle surrounded by a film layer (e.g., asolvent resistant film), can be any active pharmaceutical ingredientdesired to be administered orally, and may in particular be a type ofactive pharmaceutical ingredient that is commonly susceptible to abuse.Examples of active pharmaceutical ingredients that are considered to becommonly susceptible to abuse include psychoactive drugs, tranquilizers,sedative hypnotics, anxiolytics, stimulants, depressants, and narcoticanalgesics, among others. Certain more specific classes of drugscommonly abused includes opioids, barbiturates, benzodiadepines,amphetamines, as well as many other drugs that are known to causepsychological or physical dependence.

Dosage forms of the present description can be useful as immediaterelease dosage forms, and may also include abuse deterrent features asdescribed. The abuse deterrent features can discourage or prevent abuseby nasal insufflation, by injection, and can also be effective toprevent or significantly limit the success of abuse by the commonmethods (especially with immediate release oral dosage forms) of orallytaking multiple dosage form units together. The final mode of abuse(sometimes referred to herein as “multi-tablet dosing”) is oftenparticularly difficult to deter, especially in immediate release oraldosage forms, making these described dosage forms particularly useful asabuse-resistant oral immediate release dosage forms.

Embodiments of the described dosage forms can be effective in theabsence of other types of abuse deterrent features such as nasalirritants, emetic agents, bittering agents, and effervescent agents, toinhibit nasal insufflation or other forms of abuse, or the inclusion ofdrug antagonists of the subject drug.

In one aspect, the invention relates to an immediate release dosage formthat includes core-shell particles. The core-shell particles include: aninner core containing a gelling polymer; at least one layer surroundingthe core, the at least one layer including a film layer surrounding thecore; and an active pharmaceutical ingredient. The active pharmaceuticalingredient is also surrounded by the film layer that surrounds the core.

In another aspect, the invention relates to an immediate release dosageform that includes core-shell particles. The core-shell particlesincludes a core and an active pharmaceutical layer surrounding the core.The active pharmaceutical layer contains an active pharmaceuticalingredient. The core contains less than 5 weight percent of a totalamount of the active pharmaceutical ingredient in the core-shellparticles.

In yet another aspect the invention relates to an immediate releasedosage form that contains core-shell particles. The core-shell particlesinclude: a core and an active pharmaceutical ingredient. The dosage formfurther includes a matrix. The matrix includes disintegrant and anadditional amount of gelling polymer.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A, 1B, and 1C illustrate embodiments of core-shell particles asdescribed, in cross section.

FIGS. 2A and 2B illustrate embodiments of core-shell particles asdescribed, in cross section.

FIG. 3 is a perspective view of an embodiment of a dosage form asdescribed.

FIG. 4 shows a plot of Multiple Tablet oral Abuse Resistance(Supratherapeutic Dosing)—Dissolution of Hydrocodone Bitartrate in 0.1NHCl media as a function of time.

FIG. 5 shows a plot of multiple tablet oral abuse resistance(supratherpeutic dosing)—dissolution of acetaminophen in 0.1N HCl mediaas a function of time.

FIG. 6 shows a plot of multiple tablet oral abuse resistance(supratherapeutic dosing)—dissolution of hydrocodone bitartrate in 0.1NHCl media as a function of time.

FIG. 7 shows a plot of multiple tablet oral abuse resistance(supratherpeutic dosing)—dissolution of acetaminophen in 0.1N HCl mediaas a function of time

FIG. 8 shows a plot of multiple tablet oral abuse resistance(supratherapeutic dosing)—dissolution of hydrocodone bitartrate in 0.1NHCl media as a function of time.

FIG. 9 shows a plot of multiple tablet oral abuse resistance(supratherpeutic dosing)—dissolution of acetaminophen in 0.1N HCl mediaas a function of time.

DETAILED DESCRIPTION

The present description relates to immediate release dosage forms thatinclude one or more abuse deterrent features for reducing the potentialfor a) parenteral abuse, b) abuse by nasal insufflation (“snorting”),and c) abuse by simultaneous oral ingestion of multiple oral dosage formunits (tablets or capsules) of a drug. These abuse deterrent featuresare achieved by preparing the dosage form to include certain structuralfeatures and certain ingredients that have now been determined toeffectively prevent an abuser from realizing the intended biologicaleffect of the drug abuse by using certain presently-common methods usedto abuse the API. Advantageously, a dosage form prepared to contain oneor more of the described abuse deterrent features, as a deterrent toabuse of one or more API that is commonly susceptible to abuse, canstill be constructed to provide immediate release of the one or more APIupon normal therapeutic use by oral ingestion.

As used herein, expressions such as “abuse deterrent” and “preventing”or “deterring” or “inhibiting” practices and processes associated withthe abuse and overdose of drugs, relate to features of the claimedformulations that provide significant physical and chemical impedimentsto these practices and processes. The objective in such deterrenceincludes both making abuse practices significantly more difficult tocarry out, and making any product resulting from an attempt to carry outsuch abuse practices on the claimed formulations significantly lessdesirable, less profitable, and less abusable to the potential abuser.

The term “immediate release” refers to a dosage form that upon oralingestion by a human releases substantially all of a contained activepharmaceutical ingredient into a gastrointestinal tract for biologicaluptake in a short time. In vitro methods of measuring a release profileof a dosage form, for the purpose of determining whether a dosage formexhibits an immediate release or dissolution profile, are known in thepharmaceutical arts. By such methods, examples of dosage forms asdescribed herein can be measured to be capable of releasingsubstantially all of a total amount of at least one type of activepharmaceutical ingredient (e.g., an API commonly susceptible to abuse)contained in the dosage form (e.g., at least 75, 80, or 90 weightpercent of the total amount of the API in a dosage form) into a solution(e.g., acidic aqueous solution) of a suitable pH within 240 minutes,e.g., in less than 180 minutes, less than 90 minutes, or less than 60,30, 15, or 5 minutes. For example, a release profile of a dosage form ofthe present description may be measured by a method that exposes thedosage form to a volume of up to 900 milliliters (e.g., 300 milliliters,or 900 milliliters, based on various test methods) of hydrochloric acid(0.01 to 0.1N) (e.g., aqueous hydrochloric acid) at a pH of from 1 to 2,and at a temperature of 37 degrees Celsius.

Dosage forms as described can be formulated to provide an immediaterelease profile of an API, and can also be prepared to include effectiveor advantageous abuse deterrent features that are effective to deterabuse of the same API (e.g., one that is commonly susceptible to abuse)that exhibits the immediate release profile. The combination ofimmediate release of an API with broad abuse resistance of the same APIfor multiple abuse modalities including multi-tablet dosing, asdescribed herein, is not believed to be previously known. Moreparticularly, dosage forms as described herein can provide an immediaterelease profile of an API, and can at the same time include abusedeterrent features that provide general abuse deterrence or abuseresistance of the same API. The dosage forms can also be morespecifically characterized as resistant to certain common methods ofabuse, such as 1) abuse by injection (e.g., by steps that includegrinding a dosage form and dissolving API of the dosage form), 2) abuseby nasal insufflation (e.g., also by grinding and optionally dissolvingAPI of a dosage form), and 3) abuse by multi-tablet dosing by oralconsumption, meaning simultaneous oral ingestion of multiple orexcessive quantities of orally administered dosage forms such as tabletsor capsules. The third mode of abuse, multi-tablet dosing, isparticularly common with immediate release dosage forms and isparticularly difficult to defend against by design of a dosage formstructure or by formulation. Accordingly, that the presently-describeddosage forms can be effective to prevent or deter abuse (or evenaccidental overdose) by the mode of multi-tablet dosing can be aparticularly useful feature of the dosage forms described herein.

In vitro testing of exemplary dosage forms as described herein indicatesthat exemplary dosage forms provide deterrence against abuse bymulti-tablet dosing. More specifically, in vitro testing of exemplarydosage forms was performed by conducting dissolution testing of one ormore dosage forms (tablets) in 300 milliliters of 0.1NHCL maintained at37 degrees Celsius using a 50 RPM paddle speed. See, Example 26 (a) andFIGS. 4 and 5 herein. As shown at FIGS. 4, 5, 6, 7, 8 and 9, the amount(percentage per tablet) of API (opioid) or APAP (acetaminophen) releasedin the media is reduced with an increase in the number of tablets. Thedata also suggest that the tested dosage forms are effective to preventincreased levels of API uptake in an individual who would accidentallyingest multiple tablets, preventing or reducing the risk of anunintentional overdose of the API. (In FIGS. 4 and 5, the 1 tablet and 2tablet dosage forms are as prepared in Example 3, infra, and the 5tablet, 8 tablet, and 12 tablet dosage forms are as prepared in Example5, infra. The tablets used in FIGS. 6, 7, 8 and 9 are as prepared as perExample 17.)

As one type of abuse deterrent feature, a dosage form as described caninclude one or more gelling polymers. A gelling polymer can act as anabuse deterrent feature by compromising abuse practices wherein anactive pharmaceutical ingredient of a dosage form is being dissolved ina small volume of solvent or being accessible or easily isolatable ifcombined with solvent with the gelling polymer also present. A gellingpolymer can also deter or prevent abuse of an API in a dosage form byincreasing the viscosity of a combination of the ground dosage form withsolvent (especially a “small volume” of solvent) to a viscosity that issufficiently high to prevent the combination or the API from being takenup by and injected using a syringe. A preferred gelling polymercontained in a ground dosage form, when exposed to a limited volume (or“small volume”) of solvent such as a C₁₋₄ alcohol (e.g., ethanol ormethanol) or water, can form a non-injectable mass ranging from aninsoluble mass, to a gel, to a viscous slurry, each of which exhibits aviscosity that substantially prevents either uptake by or injection froma needle of a hypodermic syringe.

Suitable gelling polymers include one or a combination of polymers that,as part of a dosage form, upon contact of the dosage form with a smallvolume of solvent, will absorb the solvent and swell to form a viscousor semi-viscous substance that significantly reduces or minimizes theamount of free solvent that can contain an amount of a solubilized APIand that can be drawn into a syringe. The gelled polymer can also reducethe overall amount of drug extractable with the solvent by entrappingthe drug in a gel matrix.

The gelling polymer can be present in the dosage form at a location andin an amount that together allow the gelling polymer to produce aviscous gel in the event of an abuser grinding the dosage form andcombining the crushed dosage form with a solvent. On the other hand, thegelling polymer, as present in the dosage form, will preferably notinterfere with desired dissolution of the dosage form, the desiredrelease (immediate release) of API from the dosage form, or the uptakeof the API by a patient ingesting the intact immediate release dosageform for an intended therapeutic purpose. An exemplary location for thegelling polymer is in a coated particle that also includes activepharmaceutical ingredient, such as in a core or in a layer coated tosurround the core; wherein an amount of active pharmaceutical ingredientis contained in either the core, or a layer coated to surround the core,or is contained in both. Another exemplary location is within a matrixused to form a compressed tablet, a capsule (e.g., a compressedcapsule), a caplet, or another type of dosage form that contains acoated particle that contains active pharmaceutical ingredient.

The gelling polymer can be present in a dosage form at any desiredamount and at any portion of, or location in a dosage form structure.The amount of gelling polymer can be any useful amount, meaning anamount that can produce an abuse-resistant viscous mixture or gel if thedosage form is crushed, ground, powdered, etc., and mixed with solvent.A useful amount of total gelling polymer in a dosage form may be in arange from 0.5 to 90 weight percent gelling polymer based on a totalweight of the dosage form, e.g., from 0.7 to 20, or 2 to 15 weightpercent gelling polymer based on total weight of the dosage form.

These amounts of total gelling polymer can be present in one or morelocations of the dosage form, to achieve the specified total amount,such as in a portion at a coated particle (e.g., core), a matrix (e.g.,compressed matrix) structure that supports and contains the coatedparticles, or in both the coated particles and the matrix.

A core (uncoated) of a core-shell particle can contain any useful amountof gelling polymer, such from 0 up to and including 100 percent gellingpolymer in a core of a core-shell particle, e.g., from 10 to 95 weightpercent gelling polymer based on a total weight of the core, such asfrom 40 to 85 or 50 to 75 weight percent gelling polymer based on totalweight core.

Described in terms of total weight of a dosage form, an amount ofgelling polymer present in a core of a core shell polymer may be, e.g.,in a range from 0.5 to 15 weight percent gelling polymer (present in thecore) per total weight of the dosage form, such as from 1 to 10 weightpercent gelling polymer (present in the core) per total weight dosageform. An amount of gelling polymer present in a matrix of a dosage formmay be any desired amount, such as an amount in a range from 0.5 to 15weight percent gelling polymer (as excipient in a matrix) based on atotal weight of the dosage form, such as from 1 to 10 weight percentgelling polymer (present as excipient in a matrix) based on total weightdosage form.

A useful gelling polymer can be any polymeric material that exhibits theability to retain a significant fraction of adsorbed solvent in itsmolecular structure, e.g., the solvent being a solvent otherwise usefulby an abuser to extract API from a dosage form or a crushed or powdereddosage form, the solvent for example being water or a C₁ to C₄ alcoholsuch as ethanol or methanol, etc. Examples of gelling polymers includematerials that can swell or expand to a very high degree when placed incontact with such a solvent. The swelling or expansion may cause thegelling polymer to experience from a two- to one-thousand-fold volumeincrease from a dry state. More specific examples of gelling polymersinclude swellable polymers sometimes referred to as osmopolymers orhydrogels. The gelling polymer may be non-cross-linked, lightlycrosslinked, or highly crosslinked. The crosslinking may involvecovalent or ionic bonds with the polymer possessing the ability to swellin the presence of a solvent, and when cross-linked will not dissolve inthe solvent.

A gelling polymer, upon dissolution or dispersion in an aqueous solutionor dispersion (e.g., water) at a concentration of 2% w/w (based on thedry material), creates a solution/dispersion with a viscosity of fromabout 100 to about 200,000 mPa·s (e.g., 4,000 to 175,000 mPa·s, and4,000 to 50,000 mPa·s) as measured at 20 degrees Celsius (+/−0.2 degreeCelsius) using the analysis method described in the USP 33 monograph forhypromellose (incorporated herein by reference).

Generally suitable gelling polymers include pharmaceutically acceptablepolymers that undergo an increase in viscosity upon contact with asolvent, as described. Various examples of polymers are known to beuseful in this manner, generally including natural and syntheticstarches (i.e., modified or pregelatinized modified starch), natural andsynthetic celluloses, acrylates, and polyalkylene oxides. Examples ofnatural starches include natural starches include corn starch, potatostarch, rice starch, tapioca starch and wheat starch, hydroxypropylstarch such as hydroxypropyl corn starch, hydroxypropyl pea starch andhydropropyl potato starch (derivative of natural starch). Examples ofsynthetic starches, i.e., modified or pregelatinized modified starch,include acetylated distarch adipate, waxy maize basis, acid-treatedmaize starch, acid-treated waxy maize starch, distarch phosphate, waxymaize basis, oxidized waxy maize starch, and sodium octenyl succinatestarch. Examples of celluloses include carboxymethylcellulose calcium,carboxymethylcellulose sodium, ethycellulose, methylcellulose, celluloseethers such as hydroxypropyl cellulose, hydroxyethylcellulose,hydroxyethylmethyl cellulose, hydroxypropyl methyl cellulose,carboxymethylcellulose sodium, and low substituted hydroxypropylcellulose. Examples of acrylates include Eudragit RS, RL, NE, NM.Examples of polyalkylene oxides include polyethylene oxide such asPOLYOX N10, N80, N60K, WSR-1105 LEO, or WSR-301 LEO, or WSR-303 LEO.

Accordingly, examples of suitable gelling polymers include polyethyleneoxide, polyvinyl alcohol, hydroxypropyl methyl cellulose, hydroxypropylcellulose, methyl cellulose, hydroxyethylmethylcellulose, sodiumcarboxymethylcellulose, hydroxyethylcellulose, polyacrylic acid andpolyvinyl carboxy polymers such as those commercially available underthe trade name Carbopol®, and other high molecular weight polymerscapable of attaining a viscosity level effective to prevent uptake in asyringe, if combined with a small volume of solvent as described.

Other examples of suitable gelling polymers can include, if ofsufficiently high molecular weight: ethylcellulose, cellulose acetate,cellulose acetate propionate, cellulose acetate butyrate, celluloseacetate phthalate and cellulose triacetate, cellulose ether, celluloseester, cellulose ester ether, cellulose; acrylic resins comprisingcopolymers synthesized from acrylic and methacrylic acid esters, forexample acrylic acid and methacrylic acid copolymers, methylmethacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylicacid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate,poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkylmethacrylate copolymer, poly(methacrylic acid anhydride), and glycidylmethacrylate copolymers.

Exemplary gelling polymers can include natural polymers such as thosederived from a plant or animal, as well as polymers preparedsynthetically. Examples include polyhydroalkylcellulose having amolecular weight greater than 50,000; poly(hydroxy-alkylmethacrylate)having a molecular weight of from 5,000 to 5,000,000;poly(vinyl-pyrrolidone) having a molecular weight of from 100,000 to3,000,000; anionic and cationic hydrogels; poly(electrolyte) complexes;poly(vinyl alcohol) having a low acetate residual; a swellable mixtureof agar and carboxymethyl cellulose; a swellable composition comprisingmethyl cellulose mixed with a sparingly cross-linked agar; a polyetherhaving a molecular weight of from 10,000 to 6,000,000; water-swellablecopolymer produced by a dispersion of finely divided copolymer of maleicanhydride with styrene, ethylene, propylene, or isobutylene; waterswellable polymer of N-vinyl lactams; and the like.

Other polymers useful as a gelling polymer include pectin having amolecular weight ranging from 30,000 to 300,000; polysaccharides such asagar, acacia, karaya, tragacanth, algins and guar; polyacrylamides;water-swellable indene maleic anhydride polymers; Good-rite® polyacrylicacid having a molecular weight of 80,000 to 200,000; Polyox®polyethylene oxide polymers having a molecular weight of 100,000 to7,000,000; starch graft copolymers; Aqua-Keep® acrylate polymers withwater absorbability of 400 times its original weight; diesters ofpolyglucan; a mixture of cross-linked polyvinyl alcohol andpoly(-vinyl-2-pyrrolidone); poly(ethylene glycol) having a molecularweight of 4,000 to 100,000.

In various specific embodiments, a gelling polymer may be, or mayinclude, hydroxypropyl methyl cellulose (e.g., Hypromellose or HPMC),and hydroxy methyl cellulose, methyl cellulose, hydroxyethylmethylcellulose, and sodium carboxymethyl cellulose. The hydroxypropyl methylcellulose can have a molecular weight ranging from 10,000 to 1,500,000.Examples of suitable, commercially available hydroxypropylmethylcellulose polymers include HPMC K100M, Methocel K100LV andMethocel K4M.

A specific class of gelling polymer is the class of carbomer polymers,which are polymers derived from acrylic acid (e.g., acrylic acidhomopolymers) and crosslinked with polyalcohol allyl ethers, e.g.,crosslinked with polyalkenyl ethers of pentaerythritol or sucrose.Carbomer polymers are hydrophilic and are not substantially soluble inwater. Rather, these polymers swell when dispersed in water forming acolloidal, mucilage-like dispersion. Carboxyl groups provided by acrylicacid residues of the polymer backbone are responsible for certainbehavior of the polymers. Particles of this polymer can be viewed as anetwork structure of polymer chains interconnected by crosslinks. Thestructure can swell in water by up to one thousand times of an original(dry) volume (and ten times an original diameter of polymer particles)to form a gel when exposed to a pH environment above 4-6. The pKa ofthese polymers can be 6±0.5. Accordingly, carboxylate groups pendantfrom the polymer backbone can ionize at a pH above 6, producing arepulsion between the negatively-charged particles, which adds to theswelling of the polymer if exposed to solvent at this pH range. For thisreason, a dosage form as described herein can preferably include a pHadjuster in an amount and location within the dosage form to raise thepH of a carbomer polymer to at least 6, to substantially neutralize thecarboxylate groups. Carbomer polymers are often referred to in the artusing alternative terminology such as, for example, carbomerhomopolymer, acrylic acid polymers, carbomera, Carbopol, carboxypolymethylene, carboxyvinyl polymer, Pemulen, polyacrylic acid, andpoly(acrylic acid), The USP-NF lists three umbrella monographs i.e. for“carbomer copolymer,” for “carbomer homopolymer,” and for “carbomerinterpolymer.”

Certain carbopol (carbomer) polymers that may be useful as a gellingpolymer can have an average equivalent weight of 76 per carboxyl group.Examples of suitable commercially available carbomers include Carbopol®934, 934P NF, Carbopol® 974P NF and Carbopol® 971P NF, Carbopol® 940,and Carbopol® 941, Carbopol® 71G, commercially available from Lubrizol.Examples of such polymers are described in U.S. Pat. Nos. 2,798,053 and2,909,462, the entireties of which are incorporated herein by reference.Theoretical molecular weight ranges of Carbopol® products are in a rangefrom 700,000 to 3 billion, theoretical estimation. For dosage forms asdescribed herein, a gelling polymer (e.g., Carbopol®) can have amolecular weight and viscosity-increasing performance that will reduceor substantially inhibit an ability of an abuser to extract API from acombination of dosage form and a small volume of solvent, as described,while also being capable of being processed into a compressed dosageform.

A gelling polymer can also be characterized by viscosity of a solutionprepared from the gelling polymer. Product information for commerciallyavailable Carbopol® polymers reports that viscosities of differentCarbopol® polymers are as follows:

Viscosity specified Type of Carbomer (cP) Carbomer Homopolymer Type A 4,000-11,000 (compendial name for Carbopol 71G, Carbopol 971P andCarbopol 981) Carbomer Homopolymer Type B 25,000-45,000 (compendial namefor Carbopol 934P, and Carbopol 934) Carbomer Homopolymer Type C40,000-60,000 (compendial name for Carbopol 980) (Type A and Type Bviscosities measured using a Brookfield RVT, 20 rpm, neutralized to pH7.3-7.8, 0.5 weight percent mucilage, spindle #5.)

Another example of a type of preferred gelling polymer is the class ofxanthan gum polymers, which includes natural polymers useful ashydrocolloids, and derived from fermentation of a carbohydrate. Amolecular weight of a Xanthan gum may be approximately 1,000,000.Xanthan gum has been shown to provide particularly useful extractionresistance in a dosage form as described, and therefore may be preferredin dosage forms as described, especially if present in an amount of atleast 2 or 3 weight percent based on a total weight of a dosage form.

Without limiting the scope of useful gelling polymers to any specifictype or molecular weight, examples of useful gelling polymers, anduseful respective molecular weights, are shown at Table below.

Gelling Polymer Weight Average Molecular Weight Carbomer 700,000 to 3billion (estimated) HPMC 2910 K types  164,000-1,200,000 HPMC 2910 Etypes 20,000-746,000 hydroxyethylcellulose   90,000-1,300,000ethylcellulose 75,000-215,000 carboxymethylcellulose 49,000-725,000sodium carboxymethylcellulose 49,000-725,000 povidone   4,000-1,300,000copovidone   47,000 hydroxypropyl cellulose   40,000-1,150,000 xanthangum 1,000,000 polyethylene oxide Average molecular wt: 100,000-7,000,000

The dosage form may optionally include another abuse deterrent in theform of a wax, such as a wax/fat material as described in Applicant'sco-pending United States patent application 2008/0311205, the entiretyof which is incorporated herein by reference. The wax can be a solid waxmaterial that is present in the dosage form at a location that inhibitsan abuser from crushing, grinding, or otherwise forming the dosage forminto a ground powder that might be abused by a nasal insufflation mode,or from which active pharmaceutical agent can be easily accessed andremoved such as by dissolution or extraction using a solvent.

The wax may be present in the dosage form at a location and in an amountto also not interfere with desired uptake of the active pharmaceuticalingredient by a patient upon oral ingestion, in an immediate releasedosage form. An exemplary location is at a core of a core-shellparticle, especially a core that also contains gelling polymer and thateither may or may not contain active pharmaceutical ingredient. Waxlocated at a core of a particle (e.g., a core-shell particle) that alsoincludes active pharmaceutical ingredient (e.g., at a layer covering thecore, or within the core) will become mixed with the activepharmaceutical ingredient upon crushing or grinding, etc., of theparticle. When the wax is mixed with the active pharmaceuticalingredient, the active ingredient is inhibited or prevented frombecoming thereafter dissolved in a solvent such as water or otherwiseefficiently accessed by an abuser.

A core (uncoated) of a core-shell particle can contain any useful amountof wax, up to and including 100 percent wax, e.g., from 0.1 to 85 weightpercent wax based on a total weight of the core, such as from 15 to 60or 25 to 50 weight percent wax based on total weight core. Moregenerally, a useful amount of wax in a dosage form (e.g., with the waxlocated in the coated particle, e.g., in the core) may be in a rangefrom 0.05 to 15 weight percent wax based on total weight of a dosageform, e.g., from 0.1 to 10 or from 2 to 5 weight percent wax based ontotal weight of the dosage form.

The wax may be a wax (e.g., fat) material that is generally hydrophobicand that may be either solid or liquid at room temperature, preferablysolid at room temperature (25 degrees Celsius). Generally useful fatsinclude those hydrophobic materials that are fatty acid-based compoundsgenerally having a hydrophilic/lipophilic balance (HLB) of 6 or less,more preferably 4 or less, and most preferably 2 or less. A fat can haveany melting temperature, with preferred fats being solid at roomtemperature and having a melting point that is at least 30 degreesCelsius, e.g., at least 40 degrees Celsius, e.g., at least 50 degreesCelsius. Useful fats include fatty acids and fatty esters that may besubstituted or unsubstituted, saturated or unsaturated, and that have achain length of at least 10, 12, or 14 carbons. The esters may include afatty acid group bound to any of an alcohol, glycol, or glycerol. Withregard to glycercols, for example, mono-, di-, and tri-fatty substitutedglycerols can be useful as well as mixtures thereof.

Suitable wax ingredients include fatty aced esters, glycerol fatty acidesters, fatty glyceride derivatives, waxes, and fatty alcohols such as,for example, glycerol behenate (a.k.a. glyceryl behenate, glycerinbehenate, glycerol docosanoate) (e.g., COMPRITOL®), glycerolpalmitostearate (PRECIROL®), glycerol monostearate, stearoylmacroglycerides (GELUCIRE® 50/13). Other waxes more generally includeinsect and animal waxes, vegetable waxes, mineral waxes, petroleumwaxes, and synthetic waxes; particularly examples include beeswax,carnauba wax, condelilla wax, montan wax, ouricury wax, rice-bran wax,jojoba wax, microcrystalline wax, cetyl ester wax, cetyl alcohol,anionic emulsifying wax, nonionic emulsifying wax and paraffin wax.

The dosage form may optionally include another abuse deterrent in theform of a filler or binder material provided in a manner to compromisingabuse practices wherein an abuser crushes, grinds, or otherwise formsthe dosage form into a ground powder that might be abused by a nasalinsufflation mode, or from which active pharmaceutical agent can beeasily accessed and removed such as by dissolution or extraction using asolvent.

The binder or filler may be present in the dosage form at a location andin an amount to also not interfere with desired uptake of the activepharmaceutical ingredient by a patient upon oral ingestion, in animmediate release dosage form. An exemplary location is at a core of acore-shell particle. Suitable filler or binder located at a core of aparticle (e.g., a core-shell particle) that also includes activepharmaceutical ingredient (e.g., at a layer covering the core, or withinthe core) will become mixed with the active pharmaceutical ingredientupon crushing or grinding, etc., of the particle. When a filler orbinder is mixed with the active pharmaceutical ingredient, the activepharmaceutical ingredient is inhibiting or prevented from becomingthereafter dissolved in a solvent such as water or otherwise efficientlyaccessed by an abuser.

When present within a core or particle of a dosage form, e.g., at a coreof a core-shell particle, filler or binder may be present in any usefulamount, such from 0 up to and including 100 percent filler or binder(singly or in combination) in a core of a core-shell particle, e.g.,from 10 to 95 weight percent filler or binder (singly or in combination)based on total weight of the core, such as from 40 to 85 or 50 to 75weight percent based on total weight core. Examples of cores thatcontain high levels of filler include spherical particles that contain100 percent sugar, and spherical particles that contain 100 percentmicrocrystalline cellulose. Inert spherical filler products such asthese, having useful particle sizes, are commercially available underthe trade name Celphere®, and under the trade name Suglets® (sugarspheres, also containing starch), including as follows: CELPHERE SCP-100(Particle size (μm) 75-212); CELPHERE SCP-102 (Particle size (μm)106-212); CELPHERE SCP-203 (Particle size (μm) 150-300); CELPHERESCP-305 (Particle size (μm) 300-500); CELPHERE SCP-507 (Particle size(μm) 500-710); CELPHERE SCP-708 (Particle size (μm) 710-850). Theparticles sizes of these can be considered to be useful for any core asdescribed herein, prepared of any single filler, gelling polymer,binder, any combination thereof, or any single or combination ofmaterials combined with API.

Another optional abuse deterrent feature that can be included in adosage form as described is a film layer or coating as part of acore-shell particle that is located over and surrounds an API. The filmlayer can be any film layer capable of being applied as a film layer tocore-shell particles, to surround API. The film layer may be preparedfrom and will include any pharmaceutically acceptable film formingpolymer material, such as one or more of a binder (e.g. as describedherein, such as hydroxypropyl cellulose, poly(methyl methacrylates),ethyl cellulose, hydroxypropyl methyl cellulose, hydroxyl methylcellulose, polyvinyl alcohol, and the like), a solvent-resistant layer,and a pH-sensitive layer (also sometimes referred to as a reverseenteric material or layer), e.g., Eudragit® RL. The film layer mayinclude any one of these materials alone (e.g., a film layer may include100 percent of a single one of these types of materials), or a filmlayer may include a combination of two or more of these types ofmaterials.

A solvent-resistant layer is a film layer that retards or preventrelease of a drug in a solvent (e.g., one or more of water, ethanol, andmethanol) while still allowing the drug to release normally in agastrointestinal tract when ingested as an immediate release oral dosageform. This type of abuse deterrent feature, e.g., solvent-resistantfilm, can inhibit access to an API of a dosage form by preventing orimpeding an abuser from dissolving an intact or powdered dosage form ina solvent type that is often used by an abuser (e.g., water, ethanol,methanol). At the same time, the solvent-resistant film can dissolve ina human gastrointestinal tract with sufficient rapidity to allow for animmediate release profile. As an abuse deterrent feature this type ofsolvent-resistant film covers and encloses API of a core-shell particleand acts as a film barrier or retardant to prevent or retard access tothe API by use of solvent.

A solvent-resistant film is one that does not readily or immediatelydissolve in a small volume of a solvent of the type often used by anabuser to dissolve an API, such as any one of water or a C₁-C₄ alcoholsuch as ethanol or methanol. A “small volume” refers to an amount ofsuch a solvent that can contain an amount of dissolved API that issufficiently concentrated to be useful to an abuser to realize theintended biological effect of the drug abuse, and that is also capableof being administered for abuse of the API, e.g., a volume that cancontain an amount (concentration) of API that is effective to achieve adesired “high” if administered by injection or nasal insufflation, thevolume also being sufficiently small to allow the volume to beadministered by injection or nasal insufflation. For a dosage form to beuseful for abuse as such, an API in the dosage form must be capable ofbeing accessed and dissolved at sufficient concentration by an abuserwithout undue complication, into a “small volume” of solvent, which is avolume that can be administered by injection or by nasal insufflation.Generally, a “small volume” of solvent means 50 milliliters or less, or20 milliliters or less, or 10 milliliters or less, or 5 milliliters orless (volumes which could be injected or used for nasal insufflation).

A solvent-resistant film layer can be a film placed on a core-shellparticle that is difficult to dissolve in a “small volume” of water or aC₁-C₄ alcohol such as ethanol or methanol, e.g., that does notimmediately dissolve in one or more of water or any one of a C₁-C₄alcohol such as methanol or ethanol. The solvent-resistant film therebyretards or prevents an abuser from accessing an API portion of acore-shell particle if the core-shell particle is placed in one of thesesolvents. The solvent-resistant film need not be completely orsubstantially insoluble in any one of these solvents, or in all of thesolvents, and it must be capable of allowing the API to be accessed withsufficient rapidity, in a gastrointestinal tract, for the dosage form tobe useful as an immediate release dosage form.

A particular example of a solvent-resistant film is a film that exhibitssolubility properties that depend on the pH of a solvent. An example ofa solvent-resistant film may be a film that is substantially orcompletely insoluble at a pH that is greater than a pH condition of ahuman stomach, and that is sufficiently soluble at a pH condition of astomach (and gastrointestinal tract) to allow the film to dissolve andrelease API with sufficient rapidity that the dosage form can be usefulas an immediate release oral dosage form. A pH-sensitive layer is a typeof solvent-resistant film, and can be disposed in a dosage form tosurround an active pharmaceutical ingredient and inhibit or preventaccess to and dissolution of the active pharmaceutical ingredient in asolvent outside of a stomach (e.g., at a neutral pH environment), whilestill allowing the active pharmaceutical ingredient to be efficientlyreleased from an immediate release dosage form at a lower pH environmentof a user's stomach. This type of abuse deterrent feature can prevent orsignificantly impede an abuser's access to an active pharmaceuticalagent of a dosage form (e.g., at the core of a core-shell particle or ina layer disposed on the core, or in both the core and the layer disposedon the core) by use of a solvent that is outside of a stomach and thatdoes not have a relatively acidic pH, such as water or a C₁-C₄ alcoholsuch as ethanol, methanol, etc., or a mixture thereof, having a pH thatis higher than a pH found in a human stomach, for example a pH greaterthan 4; greater than 5; or greater than 5.5; or greater than 6.

A pH-sensitive layer may be useful as a solvent-resistant film, placedin a dosage form as a layer of a core-shell particle to surround, cover,or enclose a portion of the core-shell particle that contains activepharmaceutical ingredient. For example in a core-shell particle, anactive pharmaceutical ingredient may be located as desired at a core orat a layer outside of an uncoated or coated core; a solvent-resistantfilm in the form of a pH-sensitive layer may be disposed as a separatelayer surrounding or covering the portion of the core-shell particlethat contains the active pharmaceutical ingredient. The pH-sensitivelayer may be in direct contact with (adjacent to) a core or a layer thatincludes active pharmaceutical ingredient; alternately a core-shellparticle may include one or more intermediate layers between apH-sensitive layer and a core or layer that includes activepharmaceutical ingredient.

A useful pH-sensitive layer may include a polymer or other material thatcan be placed as a layer of a particle as described herein, such as tocover a more inner layer or core that contains active pharmaceuticalingredient, to form a pH-sensitive film surrounding or covering activepharmaceutical ingredient. The pH-sensitive film can be solubilized byexposure to a liquid that exhibits a pH that may be present in a stomachof a user of the dosage form, such as a pH below 6 or below 5.5. Tofunction as an abuse deterrent feature, i.e., to inhibit or preventefficient access to the active pharmaceutical ingredient by exposing thedosage form (optionally ground or powdered) to an easily-availablesolvent, the pH-sensitive layer can contain polymer that is not easilyor substantially soluble at a pH that is higher than a pH found in ahuman stomach, e.g., a pH greater than 6; by being insoluble at a pHgreater than 6, the pH-sensitive polymer will not dissolve in manysolvents easily available and commonly used by an abuser to extract awater-soluble drug from a dosage form such as water, ethanol, methanol,etc.

Examples of pH-sensitive polymer useful in a pH-sensitive layer includethe class of reverse enteric polymers that contain cationic-functionalgroups and that exhibit pH-dependent solubility as described herein.Examples include polymers that contain basic functional groups such asamino groups, and that exhibit solubility at pH conditions found in a(human) stomach but not at relatively higher pH conditions, e.g., notabove a pH of 4, 5, or 5.5, or not above a pH of 6. More specificexamples of such pH-sensitive polymers include copolymers of dimethylaminoethyl methacrylates, and neutral methacrylic acid esters; e.g.,dimethyl aminoethyl methacrylate, butyl methacrylates, and methylmethacrylates, such as at a ratio of 2:1:1. Examples of such polymersare commercially available under the trade name Eudragit® E-100,Eudragit® E PO, Eudragit® E 12.5, and similar amino-functionalpH-sensitive polymers. A preferred pH-sensitive polymer is the polymerEudragit E100, but any polymer that is sufficiently hydrophilic at a lowpH and hydrophobic at a higher pH to exhibit pH-dependent solubility asdescribed, may also be effective if otherwise acceptable for use in apharmaceutical dosage form, for example as a non-toxic ingredient of anoral dosage form. Reverse enteric compositions are also described in EP1694724 B1, titled “pH Sensitive Polymer and Process for PreparationThereof.”

When present as a coating of a particle that contains activepharmaceutical ingredient, a solvent-resistant film layer may be presentat any amount useful as an abuse deterrent feature, such as in a rangefrom 0.1 to 90 weight percent of a total weight of a core-shellparticle, e.g., from 3 to 50 or 4 to 40 weight percent solvent-resistantpolymer per total weight core-shell particle. More generally, a usefulamount solvent-resistant film layer or polymer in a dosage form may bein a range from 1 to 50 weight percent solvent-resistant film layer orpolymer based on a total weight of a dosage form, e.g., from 2 to 30 orfrom 3 to 15 weight percent solvent-resistant polymer based on totalweight dosage form.

A dosage form as presently described can also preferably include adisintegrant, which functions to cause the dosage form to expand andbreak up during use, e.g., at conditions of a human stomach, to allowactive pharmaceutical ingredient of the dosage form to be released in amanner to achieve an immediate release profile. Disintegrants are knowningredients of pharmaceutical dosage forms, with various examples beingknown and commercially available. Examples of disintegrants includecompositions of or containing sodium starch glycolate, starch (e.g.,maize starch, potato starch, rice starch, tapioca starch, wheat starch,corn starch and pregelatinized starch), croscarmellose sodium,crospovidone (crosslinked polyvinyl N-pyrrolidone or PVP) (polyplasdoneXL-10), sodium starch glycolate (EXPLOTAB® or PRIMOJEL®), anycombination of two or more of the foregoing, and other pharmaceuticallyacceptable materials formed into particles having a having particlesize, density, etc., to allow processing of the disintegrant into auseful immediate release dosage form.

The disintegrant can be present in an immediate release dosage form atany location that allows the disintegrant to function as desired, toexpand within the intact dosage form, upon ingestion, to cause theingested dosage form to break apart and allow for desired immediaterelease of active pharmaceutical ingredient from the dosage form, in astomach. One useful location for a disintegrant can be as a component ofan excipient used to contain core-shell particles that contain activepharmaceutical ingredient, as described herein, in a dosage form such asa compressed tablet or capsule.

When included as an excipient of a dosage form, disintegrant may bepresent in an amount useful to achieve immediate release of an API of adosage form. Examples of useful amounts of disintegrant in an immediaterelease dosage form as described herein may be in a range from 0.5 to 50weight percent disintegrant based on a total weight of the dosage form,e.g., from 1 to 30 weight percent disintegrant based on total weight ofthe dosage form. The amount of disintegrant in a matrix of a dosage formcan be consistent with these amounts, e.g., disintegrant can be includedin a matrix (e.g., total of a dosage form that is other than the coatedparticles or API) of a dosage form in an amount in a range from 0.5 to50 weight percent disintegrant based on a total weight of the matrix,e.g., from 1 to 30 weight percent disintegrant based on total weightmatrix.

A dosage form as described can also include any of various known andconventional pharmaceutical excipients that may be useful to achievedesired processing and performance properties of an immediate releasedosage form. These excipients include fillers, binders, lubricants,glidants, coloring agents, pH-adjusters, etc., and can be included incore-shell particles or in a matrix (e.g., compressed matrix) of atablet or capsule. A more detailed description of pharmaceuticalexcipients that may also be included in the tablets of the presentinvention can be found in The Handbook of Pharmaceutical Excipients, 5thed. (2006).

A pH-adjuster can be included in an immediate release dosage form asdescribed, for example at a location to affect pH at a specific locationof the dosage form that is only a portion of a total dosage form. As anexample, a pH-adjuster in the form of a base may be included at alocation of a gelling polymer that contains acid functionalities, toneutralize the acid functionalities. The amount of pH-adjuster includedat the location of the gelling polymer can be an amount effective toneutralize the acid functionalities of the gelling polymer at thatlocation. More specifically, a component of a dosage form as describedthat includes an acid-functional gelling polymer such as a carbopol mayinclude a base in an amount and location to neutralize the acidfunctionalities of that polymer. The pH-adjuster can be located at alocation effective to cause such neutralization, e.g., at the locationof the dosage form that contains the acid-functional gelling polymer,for example at a core of a core-shell particle or as part of anexcipient that includes acid-functional gelling polymer and thatfunctions to bind particles together as a dosage form.

Examples of fillers that may be useful in an immediate release dosageform as described include lactose, starch, dextrose, sucrose, fructose,maltose, mannitol, sorbitol, kaolin, microcrystalline cellulose,powdered cellulose, calcium sulfate, calcium phosphate, dicalciumphosphate, lactitol or any combination of the foregoing. As compared tonon-filler ingredients such as gelling polymers, a filler will have amolecular weight that does not result in a substantial viscosityincrease or formation of a gel as described herein for a gellingpolymer, if combined with a solvent such as water.

A filler may be present in any portion of a dosage form as described,including a core-shell particle; the filler may be present in a core, ina layer containing an active pharmaceutical ingredient that is disposedon the core, in a solvent resistant film, at a matrix, or in two or moreof these portions of the dosage form. The filler may be present at anyone or more of these portions of a dosage form in an amount to providedesired processing or functional properties of a portion of the dosageform and of the entire dosage form. The amount of total filler in adosage form can also be as desired to provide desired functionality,including an immediate release profile, for example in an amount in arange from 0 to 80 weight percent filler based upon the total weight ofthe dosage form, e.g. from 5 to 50 percent filler based on total weightdosage form.

Examples of binders that may be included in a dosage form as describedinclude polymeric material such as alginic acid, sodiumcarboxymethylcellulose, microcrystalline cellulose, dextrin,ethylcellulose, gelatin, starch, pregelatinized starch, polyvinylalcohol, polyethylene oxide, polyvinylpyrrolidone, polyacrylamides,polyvinyloxoazolidone, polyvinylalcohols, methylcellulose, hydroxypropylcellulose, hydroxymethyl cellulose and any combination of two or more ofthese. A binder may be a water soluble material; as compared tonon-binder ingredients such as a gelling polymer, a binder is of amolecular weight that does not result in formation of a gel or a highlyviscous composition upon combining with a small volume of water. Abinder can exhibit a relatively low molecular weight as compared to agelling polymer, and a relatively lower viscosity (e.g., when measuredin a 2% aqueous solution). Polymer useful as a binder may typically havea molecular weight of less than 50,000, e.g., less than 30,000, or than10,000.

A binder may be present in any portion of a dosage form as described,including a core or a film or coating of a core-shell particle, or aspart of an excipient to contain or bind core-shells particles in adosage form. Filler may be included in a core of a core-shell particlein combination with active pharmaceutical ingredient, gelling polymer orboth; as part of an active pharmaceutical layer located over a core oranother layer of a core-shell particle; as part of a solvent-resistantfilm; or within an excipient useful to bind particles into a dosageform. A binder may be present at any one or more of these portions of animmediate release dosage form as described, in an amount to providedesired processing or functional properties in each portion of thedosage form and of the overall dosage form. The amount of total binderin a dosage form can also be as desired to provide desiredfunctionality, including immediate release functionality, for example inan amount in a range from 0.1 to 10 weight percent binder based on atotal weight of a dosage form, e.g., from 0.5 to 7 weight percent binderbased on total weight dosage form.

Examples of lubricants include inorganic materials such as talc (ahydrated magnesium silicate; polymers, such as, PEG 4000; fatty acids,such as stearic acid; fatty acid esters, such as glyceride esters (e.g.,glyceryl monostearate, glyceryl tribehenate, and glyceryl dibehenate);sugar esters (e.g., sorbitan monostearate and sucrose monopalmitate);glyceryl dibehenate (Compritol® 888 ATO); and metal salts of fatty acids(e.g., magnesium stearate, calcium stearate, and zinc stearate).Accordingly, commonly used lubricants include talc, glycerylmonostearates, calcium stearate, magnesium stearate, stearic acid,glyceryl behenate, polyethylene glycol, poloxamer and combinations ofthe foregoing. Lubricant may be included in an immediate release dosageform as described, in any useful amount, such as an amount in a rangefrom 0.1 to 10 weight percent lubricant based on a total weight of adosage form, e.g., from 0.5 to 7 weight percent lubricant based on totalweight dosage form.

Examples of glidants include colloidal silicon dioxide, untreated fumedsilica (e.g., as available under the trade name Cab-O-Sil®), andcrystalline or fused quartz. Glidant may be included in an immediaterelease dosage form as described, in any useful amount.

Examples of coloring agents include FD&C-type dyes and lakes, fruit andvegetable extracts, titanium dioxide and mixtures thereof. A coloringagent may be incorporated into a dosage form by blending the coloringagent any other ingredient. Alternately, coloring agent may be appliedto an outer surface of a dosage form.

Any active pharmaceutical ingredient alone or in combination can beincluded in an immediate release dosage form as described herein. Withabuse deterrent features as described herein, some being operative basedon specific structural or compositional features of a core-shellparticle, APIs that can be particularly useful can be those types ofactive pharmaceutical ingredients that can be subject to abuse,addiction, overdosing, or two or more of these; such APIs can be locatedin the dosage form at a location to cause the API to be subject to abusedeterrent features of the core-shell particle, e.g., at a core or innerlayer of a core-shell particle.

Drugs commonly susceptible to abuse include sedative-hypnotics,stimulants (e.g., central nervous system ((CNS) stimulants),anxiolytics, antipsychotics, dissociative anesthetics, and narcoticanalgesics including but not limited to drugs that can causepsychological or physical dependence on the drug. An API can include anytherapeutically acceptable drug salt, drug derivative, drug analog, drughomologue, or polymorph of an active pharmaceutical ingredient.

Sedative hypnotics include, for example, barbiturates, for examplephenobarbital, methobarbital, amobarbital, pentobarbital, andsecobarbital and pharmaceutically acceptable salts thereof;benzodiazepines, for example diazepam, chlorodiazepoxide, lorazepam,triazolam, temazepam, alprazolam and flurazepam and pharmaceuticallyacceptable salts thereof; phenothiazines, such as for example,alimemazine, chlorpromazine, thioridazine, and pharmaceuticallyacceptable salts thereof, and sleep medications, such as for example,zolpidem, zaleplon, and eszopiclone and pharmaceutically acceptablesalts thereof. Anxiolytics include, for example, benzodiazepines, forexample diazepam, chlordiazepoxide, estazolam, lorazepam, triazolam,alprazolam, clonazepam and flurazepam and pharmaceutically acceptablesalts thereof. CNS Stimulants include, for example, amphetamines, suchas for example, dextroamphetamine, levoamphetamine (benzadrine),methamphetamine (methadrine), pseudoephedrine, and Adderall (amphetaminemixed salts) and pharmaceutically acceptable salts thereof, andnon-amphetamine psychostimulants such as methylphenidate, modafinil andarmodafinil and pharmaceutically acceptable salts thereof. Narcoticanalgesics include opioids such as, for example, buprenorphine,butorphanol, codeine, dihydrocodeine, dihydromorphine, hydrocodone,hydromorphone, morphine, oxycodone, oxymorphone, methadone, fentanyl,meperidine, tramadol, propoxyphene, and pharmaceutically acceptablesalts thereof. Antipsychotic agents can include, for example,phenothiazines as listed above, butyrophenones, such as, for example,droperidol and haloperidol, dibenzoxazepines such as loxapine, andatypical antipsychotic agents such as aripiprazole, clozapine,olanzapine, quetiapine, risperidone ziprasidone, paliperidone andremoxipride.

Other specific drugs which may be susceptible to abuse include forexample, muscle relaxants such as for example cyclobenzaprine andpharmaceutically acceptable salts thereof, cannabinols (e.g.,Δ¹-cannabidiol. Δ²-cannabidiol, Δ³-cannabidiol, Δ^(3,7)-cannabidiol,Δ⁴-cannabidiol, Δ⁵-cannabidiol, and Δ⁶-cannabidiol); cannabinoids, suchas dronabinol, delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD),nabilone, dexanabinol, ajulemic acid, cannabinor, rimonabant andtaranabant, and pharmaceutically acceptable salts thereof; anddissociative anesthetic agents such as ketamine and Esketamine, andpharmaceutically acceptable salts thereof.

The amount of active pharmaceutical ingredient included in an immediaterelease dosage form can be any useful amount, as is known and as may befound in relevant literature such as Goodman & Gillman's, ThePharmacological Basis of Therapeutics, 9th ed. pages 219-222, 361-396,521-535 1996. For example, typical therapeutic amounts of oxycodonerange 5 mg, 10 mg, or up to 400 mg, for the hydrochloride salt. Often,when processed into a suitable immediate release dosage form, the activepharmaceutical ingredient can be present in such dosage form in anamount normally prescribed, typically 0.5 to 25 percent on a dry weightbasis, based on the total weight of the dosage form. With respect tonarcotic analgesics such as opioids in a single unit dosage form, suchas at a level from about 1 to about 500 mg, or from about 1 to about 250mg, or from about 1 to about 100 mg; for example, 2.5, 5, 7.5, 10, 15,20, or 30, milligram (mg) per dosage form unit. In other embodiments, adosage form contains any appropriate amount of an API to provide atherapeutic effect.

The present invention is also directed to methods of treatment,comprising orally administering an effective amount of the hereindescribed immediate release abuse deterrent dosage form. For example,provided herein is a method of treating or preventing pain or discomfortin a subject in need thereof by administering an effective amount of theherein described immediate release abuse deterrent dosage formcontaining an API that is a narcotic analgesic drug such as an opioiddrug.

Also provided herein is a method for treating sleep disorders in asubject in need thereof by administering an effective amount of theherein described immediate release abuse deterrent dosage formcontaining an API that is a sedative hypnotic drug such as abarbiturate,

Also provided herein is a method for treating anxiety in a subject inneed thereof by administering a an effective amount of the hereindescribed immediate release abuse deterrent dosage form containing anAPI that is an anxiolytic drug such as a benzodiazepine,

Also provided herein is a method for treating psychoses in a subject inneed thereof by administering a an effective amount of the hereindescribed immediate release abuse deterrent dosage form containing anAPI that is an antipsychotic drug such as questiapine,

An “effective amount” of when used in connection with compositiondescribed herein is an amount sufficient to produce a therapeutic resultin a subject in need thereof. For example a therapeutic result caninclude, but is not limited to treating or preventing pain, sleepdisorders, anxiety or psychotic symptomology by a subject.

A dosage form as described can optionally include one or more additionalAPIs of a type that is not commonly susceptible to abuse. Thisadditional APIs may be any suitable or desired API, such as those in theclass of non-steroidal analgesic drugs. The expression “non-steroidalanalgesic drugs” as used herein refers to drugs that include thosecommonly referred to as non-steroidal anti-inflammatory drugs, or“NSAIDS,” and acetaminophen, which is non-steroidal, but does not actvia an inflammation mechanism. Accordingly, the term “non-steroidalanalgesic drugs” would include acetaminophen, and also include NSAIDSsuch as aspirin, ibuprofen, and naproxen. The dosage form also exhibitsimmediate release properties with respect to thesenot-commonly-subject-to-abuse APIs. And these APIs can be present in thedosage form at any useful level, typically 0.5 to 25, e.g., 1 to 10weight percent of the API on a dry weight basis, based on a total weightof the dosage form, e.g., at a level of or between 5, 25, 50, 75, 100,125, 150, 175, 200, 300, 325, 500, 750 or up to or exceeding 1000milligram (mg) per dosage form unit. In other embodiments, a dosage formcontains an appropriate amount of an API to provide a therapeuticeffect.

An immediate release dosage form as described can include one or more ofthe described abuse deterrent features, alone or in combination; e.g.,one or more of: gelling polymer as part of a core-shell particle (e.g.,at a core of the core-shell particle); wax as part of a core-shellparticle (e.g., at a core of the core-shell particle); binder or filleras part of a core-shell particle (e.g., at a core of the core-shellparticle); a film layer that may optionally be a solvent-resistant film(e.g., pH-sensitive film) as part of a core-shell layer; or gellingpolymer as a component of an excipient or binder used to hold core-shellparticles together as part of in an immediate release dosage form. Withthese abuse deterrent features, other types of known abuse deterrentfeatures may not be necessary and may be specifically excluded from animmediate release dosage form as described. Certain embodiments of thedescribed dosage forms can specifically exclude other types of abusedeterrents.

In specific, some dosage forms include nasal irritant to discourage orprevent abuse by nasal insufflation. The nasal irritant can be a mucousmembrane irritant or nasal passageway irritant that, if inhaled througha nasal passageway when contained in a ground or powdered dosage form,can induce pain or irritation of the abuser's nasal passageway tissue.Examples include surfactants such as sodium lauryl sulfate, poloxamer,sorbitan monoesters, and glyceryl monooleates. Certain particularembodiments of dosage forms of the present description do not require,and can specifically exclude, nasal irritant agents such as thosedescribed above

Alternately, dosage forms can include an emetic agent, to causevomiting. Certain particular embodiments of dosage forms of the presentdescription do not require and can specifically exclude an emetic agent.

Alternately, some dosage forms include an effervescent agent that actsas a deterrent to abuse by nasal insufflation. The effervescent includesan acidic component and a basic component that release a gas such asoxygen or carbon dioxide when combined in the presence of an aqueousmedia, such as upon nasal insufflation. See, e.g., patent publication WO2013/077851, the entirety of which is incorporated herein by reference.The acid source may be, for example, citric acid, tartaric acid, malicacid, maleic acid, lactic acid, glycolic acid, ascorbic acid, fumaricacid, adipic acid, succinic acid, salts thereof, and combinationsthereof. The base may be, for example, a carbonate or bicarbonate.Dosage forms of the present description do not require, and canspecifically exclude, an effervescent in the form of an acid and a basethat can combine to a gas such as oxygen or carbon dioxide.

Still other dosage forms include a biologically active chemical compoundthat functions as an antagonist to an active pharmaceutical ingredient.An antagonist may prevent the potential abuse of a dosage form in amanner, including the method of consuming multiple or several or moredosage form units at once. Antagonist agents are compounds that block ornegate the effect of an active pharmaceutical ingredient, and areavailable and known for various classes of drugs including opioids andother pharmaceutical agents. Examples of antagonist agents for opioidsinclude compounds such as naltrexone, naloxone, nalmefene, cyclazacine,levallorphan. Specific examples of antagonist agents and methods forpreparing antagonist agents for incorporation into a dosage form areprovided in U.S. Pat. Nos. 7,682,633 and 7,658,939, which areincorporated herein by reference. According to the present description,an immediate release dosage form that includes an opioid and thatincludes one or more abuse deterrent feature as described herein (e.g.,a gelling polymer, wax, solvent-resistant film, or a combinationthereof), can be formulated to not contain and to specifically excludean agonist of an API that is also included in the dosage form, e.g., anopioid antagonist in a dosage form containing an opioid.

Referring to FIGS. 1A and 1B, a dosage form can include particles 10A,10B that contain API. The particle (e.g., coated particle or“core-shell” particle) can include a core 12 (or “uncoated core”), whichmay be coated with one or more layer, film or coating, e.g., 14, 16, orany additional layer or coating that is coated over, underneath, orintermediate to these. Particle 10A, 10B can contain one or more of theingredients described herein, such as any one or more of API (especiallyan API that is susceptible to abuse), a gelling polymer, optional wax,optional solvent-resistant layer, as well as one or more additionallayer or layers under, over, or intermediate to these layers or betweeneither layer and the core. Each layer can be present in size or amount(e.g., thickness) that will result in a useful immediate release dosageform having one or more of the presently described abuse deterrentfeatures. Other optional components of a core or layer of particle 10can be filler, binder, other excipient, or solvent (not more than aresidual amount, if any) such as water or ethanol for use in preparingthe coated particle, and that is substantially removed after formationof the core, coating, or coated particle. Examples of the core 10A, 10B,can include any amount of the different ingredients of: a gellingpolymer (e.g. from 0 to 100 percent of a core), filler as describedherein such as sugar (mannitol) or microcrystalline cellulose (e.g.,from 0 to 100 percent of a core), binder (e.g., from 0 to 100 percent ofa core), and wax (e.g., from 0 to 100 percent of a core).

While core-shell particles 10 are believed to be new and inventive,certain method steps useful to prepare these novel coated particles maybe known. Available methods include certain methods and processing stepsknown to be useful for preparing particles and coated particles in thepharmaceutical arts. A core-shell particle 10 can be prepared by aninitial step of mixing ingredients of core 12 with a solvent such aswater or ethanol and forming the mixture into a spherical core particleby known methods. The particle may be dried and separated by size, andthen one or more coating in the form of a continuous film or layer canbe applied to the core, optionally successively to produce multiplelayers surrounding the core. General processing to produce a multi-layercoated particle can include a series of steps such as compounding,mixing, granulation, wet milling, coating (by any method such asfluidized bed coating, spray coating, etc.), and one or more dryingsteps such as by use of a fluidized bed or other drying method.Intermittently between core-forming and coating steps, e.g., after adrying step, coated or uncoated particles can be sorted or separatedbased on size to produce a composition or a collection of particleshaving a desired size range and distribution.

In certain embodiments as shown at FIGS. 1A, 1B, and 1C, an immediaterelease dosage form as described can include a core-shell particle 10Athat includes a core 12A that contains only a minor amount of API orthat contains an insubstantial amount of API. Core 12A may contain lessthan 5 weight percent, e.g., less than 1 or less than 0.5 weight percentactive pharmaceutical ingredient based on a total weight of the core ofthe core-shell particle. Alternatively, core 12A may contain less than 5weight percent of a total amount of pharmaceutical ingredient in acore-shell polymer, e.g., less than 5, less than 1, or less than 0.5weight percent active pharmaceutical ingredient based on total weight ofAPI in the core-shell particle. In these embodiments a major portion ofAPI can be contained outside of core 12A, e.g., in an API layer 16,which can contain at least 50, at least 75, or at least 90 weightpercent of a total amount of the API in a core-shell polymer.

Core 12A can include binder, gelling polymer (e.g., HPMC), wax, orfiller, optionally alone or in combination, each in an amount to allowthe materials of the core to function as one or more abuse deterrentfeature as described herein. See the examples included herewith forexamples of useful amounts and ranges of amounts of these ingredients.

Referring to FIG. 1A, core 12A contains gelling polymer, wax, binder, orfiller, or any combination of these, and no API (meaning not more thanan insignificant amount, such as less than 0.5 or less than 0.1 weightpercent based on the weight of core 12A). As shown at FIGS. 1B and 1C,core 12A, not containing API, can be coated with a coating layer thatcontains API, e.g., an active pharmaceutical layer or API layer 16A. Asshown at FIG. 1B, core-shell particle 10A includes core 12A, which doesnot contain any API, and API layer 16A, which contains an amount of API,such as a total amount of API (e.g., API commonly susceptible to abuse)to be contained in a dosage form prepared from particles 10A. API layer16A can contain one or more ingredients as described herein useful toform API layer 16A as a layer over an outer surface of core 12A. (API inAPI layer 16A can be a type of API that is commonly susceptible toabuse, such as an opioid, and can account for all of or most of (e.g.,at least 70, at least 80, at least 90, or at least percent) the totalamount of that type of API in the core-shell particles and in the dosageform; in this embodiment the core can contain less than 10, less than 5,or less than 1 percent of the total amount of API in the core-shellparticles, and less than 10, 5, or 1 percent of the total amount of APIin the dosage form.) Useful non-API ingredients in an API layer caninclude a binder along with the API. The API and binder can be carriedin a solvent (e.g., water, ethanol, or both) and coated and dried toform a preferably continuous film layer on an outer surface of core 12A,i.e., API layer 16A. See the examples included herewith for examples ofuseful amounts and ranges of amounts of these ingredients.

A core-shell particle 10A can also optionally include a film layer,e.g., a solvent-resistant layer (e.g., a pH-sensitive layer) 14A asdescribed herein.

In certain alternate embodiments a dosage form as described can includea core-shell particle 10B that includes a core 12B that does contain auseful amount of API, such as an amount of API useful in an immediaterelease dosage form having one or more abuse deterrent features asdescribed herein, prepared to include particles 10B. See FIGS. 2A and2B. According to such embodiments, core 12B of particle 10B can containa gelling polymer, optional wax, optional binder or filler, and anamount of API.

Referring to FIG. 2A, core 12B contains gelling polymer, optional wax,optional binder, and API. Referring to FIG. 2B, core 12B, containingAPI, can optionally be coated with solvent-resistant layer (e.g., apH-sensitive layer) 14B as described herein for use in an immediaterelease dosage form.

A coated particle 10 that includes API can be included in any of avariety of dosage forms, examples including a compressed tablet orcompressed capsule, a suppository, capsule, caplet, pill, gel, softgelatin capsule, etc. As one example, a dosage form 12 can be preparedas a compressed tablet or compressed capsule. Tablet or capsule 12 cancontain core-shell particles 10 (e.g., 10A or 10B) distributed within amatrix 20, compressed to form the compressed tablet or capsule 12.Core-shell particles 10A or 10B can be as described herein, generally orspecifically, and can contain an amount of API suited to provide adesired dosage upon ingestion of tablet or capsule 12; e.g., matrix 20does not include any substantial amount of API.

Matrix 20 can include ingredients useful in combination with thecore-shell particles 10A, 10B, to produce an immediate release dosageform. Examples of useful excipients of an immediate release dosage formcan include ingredients that allow the dosage form to break up ordisintegrate upon ingestion and facilitate exposure to fluid in astomach, such as a useful amount of disintegrant. Examples of suchexcipients for such a dosage form can also include one or moreingredients that act as an abuse deterrent feature, such as a gellingpolymer as described herein. Other excipients can be useful forprocessing to form a compressed dosage form, and also may allow thecompressed dosage form to function as an immediate release dosage form,with one or more abuse deterrent features.

The following non-limiting examples show various dosage forms asdescribed herein. The described and exemplified dosage forms can be madefrom methods that include granulating, coating, and compressing steps asfollows.

General Procedure Granulation

-   -   1. Glyceryl behenate and hypromellose K100M are dry mixed in a        high shear granulator. Hydroalcoholic solution of ethylcellulose        is added. Alternatively the granulation can be produced through        top spraying the hydroalcoholic solution in a fluid bed        granulator.    -   2. The granules are then wet milled using a size reduction mill        (Granumill) and then dried using a fluid bed.

Layering

-   -   3. The polymer granules are then layered using Wurster fluid bed        layering process with API (or alternatively, granulated using        high shear granulation or top spray fluid bed granulation        process).

Coating

-   -   4. The layered granules are then coated using a fluid bed coater        equipped with a Wurster insert (bottom spray assembly) with        ethanolic suspension of Eudragit E100 copolymer and magnesium        stearate.

Blending and Tablet Compression

The blending, compression and bottling process for hydrocodone andacetaminophen tablets manufactured using the coated intermediate is asfollows:

-   -   1. The API-containing coated granules, APAP, crospovidone,        Carbopol 71G, sodium bicarbonate and mannitol are then added to        the blender and mixed.    -   2. Magnesium stearate is then added to the blender and mixed.        The blend is compressed into tablets using a rotary tablet        press.

Example 1 Preparation of Coated Granules

TABLE 1 Components for granule formulation Component % w/w hypromellose60 glyceryl behenate 26 ethylcellulose 14 TOTAL 100

Granules were manufactured in a high shear granulator, wherehypromellose and glyceryl behenate were dry mixed for 3 minutes. Then, a10% hydroalcoholic solution of ethylcellulose N10 was slowly added whilemaintaining the granulator impeller and chopper speed at pre-selectedvalues that provide enough shear for granule formation and growth.Solution addition was continued until the entire amount ofethylcellulose was added. The granules were then wet milled using a sizereduction mill (Granumill) and were subsequently loaded into fluid bedfor drying.

TABLE 2 Components for layered granule formulation Component % w/whydrocodone bitartrate 10 polymer granules (EC, HPMC and 85 Hypromellose2910 5 TOTAL 100The prepared granules were then layered in a bottom spray fluid bedcoater with a 12% aqueous solution of hydrocodone bitartrate and HPMC2910.

TABLE 3 Components for coated granules formulation Component % w/whydrocodone layered granules, 10% 50 Eudragit E-100 33 magnesiumstearate 17 TOTAL 100The hydrocodone bitartrate layered granules were then coated in a bottomspray fluid bed coater with 25% alcoholic suspension of Eudragit E-100copolymer and magnesium stearate. The resulting coated granules weresubsequently used for further blending and compression process.

Example 2 Hydrocodone/Acetaminophen Tablets

TABLE 4 Hydrocodone/acetaminophen Tablet Formulation Component % w/wHydrocodone coated granules 20.0 paracetamol 33.7 mannitol 10.3 carbopol5.0 microcrystalline cellulose 12.0 crospovidone 15.0 sodium bicarbonate3.0 magnesium stearate 1.0 Total 100 ¹ Contains 95% acetaminophen (APAP)and 5% gelatin

The coated granules were prepared according to Example 1 above and mixedwith paracetamol and other excipients (carbomer, crospovidone, sodiumbicarbonate, mannitol, microcrystalline cellulose) and blended in aV-blender for 30 minutes. Magnesium stearate was then added to lubricatethe blend and the mixture was blended for an additional 5 minutes priorto compressing into hydrocodone/acetaminophen tablets.

Example 3 Hydrocodone Bitartrate/Acetaminophen

TABLE 5 Hydrocodone/acetaminophen Granule Formulation Core Shellcomposition Component Location mg/tablet HPMC K100M Core 51.1 compritolCore 21.9 Ethocel Core 12 hydrocodone bitartrate API layer 10 HPMC 2910API layer 5 Eudragit E-100 Film 66.7 magnesium stearate Film 33.3 Total200

TABLE 6 Hydrocodone/acetaminophen Tablet Formulation Componentsmg/tablet Core Shell composition (above) 200 APAP 325 gelatin 12.1mannitol 42.9 carbopol 50 microcrystalline cellulose 130 crospovidone200 Sodium bicarbonate 30 magnesium stearate 10 Total 1000

TABLE 7 Hydrocodone/acetaminophen Overall Tablet composition OverallTablet composition Components mg/tablet HPMC K100M 51.1 compritol 21.9Ethocel 12 hydrocodone bitartrate 10 HPMC 2910 5 Eudragit E-100 66.7APAP* 325 gelatin 12.1 mannitol 42.9 carbopol 50 microcrystallinecellulose 130 crospovidone 200 sodium bicarbonate 30 magnesium stearate43.3 Total 1000 *acetaminophen (acetyl-para-aminophenol).Coated granules were prepared according to the procedure described inExample 1. The prepared coated granules were then mixed withacetaminophen and other excipients (carbopol, crospovidone, sodiumbicarbonate, mannitol, microcrystalline cellulose) and blended in aV-blender for 30 minutes. Magnesium stearate was then added to lubricatethe blend and the mixture was blended for an additional 5 minutes priorto compressing into hydrocodone/acetaminophen tablets.

Example 4 Hydrocodone Bitartrate/Acetaminophen

TABLE 8 Hydrocodone/acetaminophen granule composition Core Shellcomposition Component Location mg/tablet HPMC K100M core 25.5 compritolcore 10.9 Ethocel core 6 hydrocodone bitartrate API layer 5 HPMC 2910API layer 2.5 Eudragit E-100 film 33.4 magnesium stearate film 16.7Total 100

TABLE 9 Hydrocodone/acetaminophen tablets Component mg/Tab Core Shellcomposition (above) 100 APAP 325 gelatin 12.14 mannitol 34.88 carbopol50 microcrystalline cellulose 96 crospovidone 144 sodium bicarbonate 30magnesium stearate 8 Total 800.02Coated granules were prepared according to the procedure described inExample 1. The prepared coated granules were then mixed withacetaminophen and other excipients (carbopol, crospovidone, sodiumbicarbonate, mannitol, microcrystalline cellulose) and blended in aV-blender for 30 minutes. Magnesium stearate was then added to lubricatethe blend and the mixture was blended for an additional 5 minutes priorto compressing into hydrocodone/acetaminophen tablets.

TABLE 10 Hydrocodone/acetaminophen tablet composition Overall Tabletcomposition Components mg/tablet HPMC K100M 25.5 compritol 10.9 ethocel6 hydrocodone bitartrate 5 HPMC 2910 2.5 Eudragit E-100 33.4 APAP 325gelatin 12.14 mannitol 34.88 carbopol 50 microcrystalline cellulose 96crospovidone 144 sodium bicarbonate 30 magnesium stearate 24.7 Total800.02

Example 5 Hydrocodone Bitartrate/Acetaminophen

TABLE 11 Hydrocodone/acetaminophen granule composition Core Shellcomposition Component Location mg/tablet HPMC K100M core 50.1 compritolcore 21.5 ethocel core 11.8 hydrocodone bitartrate API layer 9.8 HPMC2910 API layer 4.9 Eudragit E-100 film 65.4 magnesium stearate film 32.7Total 196.2

TABLE 12 Hydrocodone/acetaminophen tablet composition Component mg/TABCore Shell composition (above) 196.1 APAP 325 gelatin 12.14 mannitol46.2 carbopol 50 microcrystalline cellulose 130 crospovidone 200 rediron oxide 0.6 sodium bicarbonate 30 magnesium stearate 10 Total 1000

Coated granules were prepared according to the procedure described inExample 1. The prepared coated granules were then mixed withacetaminophen and other excipients (carbopol, crospovidone, sodiumbicarbonate, mannitol, red iron oxide, microcrystalline cellulose) andblended in a V-blender for 30 minutes. Magnesium stearate was then addedto lubricate the blend and the mixture was blended for an additional 5minutes prior to compressing into hydrocodone/acetaminophen tablets.

TABLE 13 Hydrocodone/acetaminophen tablet composition Overall Tabletcomposition Components mg/tablet HPMC K100M 50.1 compritol 21.5 ethocel11.8 hydrocodone bitartrate 9.8 HPMC 2910 4.9 Eudragit E-100 65.4 APAP325 gelatin 12.14 mannitol 46.2 carbopol 50 microcrystalline cellulose130 crospovidone 200 red iron oxide 0.6 sodium bicarbonate 30 magnesiumstearate 42.7 Total 1000.14

Example 6 Oxycodone Hydrochloride (Single API) (Celphere Core)

TABLE 14 Oxycodone granule composition Core Shell composition ComponentsLocation mg/tablets Celphere (MCC) core 42 oxycodone hydrochloride APIlayer 5.2 HPMC 2910 API layer 1.7 Eudragit E-100 film 1.9 magnesiumstearate film 0.6 Total 51.4

Microcrystalline cellulose particles were layered in a bottom sprayfluid bed coater with a 12% aqueous solution of oxycodone hydrochlorideand HPMC 2910.

The oxycodone hydrochloride layered particles were then coated in abottom spray fluid bed coater with 25% alcoholic suspension of EudragitE-100 copolymer and magnesium stearate. The resulting coated particleswere subsequently used for further blending and compression process.

TABLE 15 Oxycodone tablet composition Component mg/TAB Core Shellcomposition (above) 51.54 lactose 96.46 microcrystalline cellulose 40crospovidone 10 magnesium stearate 2 Total 200

The coated particles were mixed with other excipients (crospovidone andlactose) and blended in a V-blender for 30 minutes. Magnesium stearatewas then added to lubricate the blend and the mixture was blended for anadditional 5 minutes prior to compressing into oxycodone tablets.

TABLE 16 Oxycodone tablet composition Overall Tablet compositionComponents mg/tablet microcrystalline cellulose 82 oxycodonehydrochloride 5.2 HPMC 2910 1.7 Eudragit E-100 1.9 lactose 96.46crospovidone 10 magnesium stearate 2.6 Total 199.86

Example 7 Hydrocodone Bitartrate/Acetaminophen (Sugar Sphere Core)

TABLE 17 Hydrocodone bitartrate granule composition Core Shellcomposition Component Location mg/tablet sugar sphere core 47.3 PEO core24.7 EPO core 20.5 hydrocodone bitartrate API layer 5 HPMC 2910 APIlayer 2.5 Eudragit E-100 film 75 magnesium stearate film 25 Total 200Sugar sphere particles were layered in a bottom spray fluid bed coaterwith an aqueous solution of hydrocodone bitartrate and HPMC 2910.The hydrocodone bitartrate layered particles were then coated in abottom spray fluid bed coater with 25% alcoholic suspension of EudragitE-100 copolymer and magnesium stearate. The resulting coated particleswere subsequently used for further blending and compression process.

TABLE 18 Hydrocodone bitartrate tablet composition mg/tablet Core Shellcomposition (above) 200 APAP 325 binder 17.8 mannitol 192.2microcrystalline cellulose 200 crospovidone 50 magnesium stearate 15Total 1000

The coated spheres were mixed with acetaminophen and other excipients(mannitol, microcrystalline cellulose, binder and crospovidone) andblended in a V-blender for 30 minutes. Magnesium stearate was then addedto lubricate the blend and the mixture was blended for an additional 5minutes prior to compressing into oxycodone tablets.

TABLE 19 Hydrocodone bitartrate tablet composition Overall Tabletcomposition Components mg/tablet sugar 47.3 PEO 24.7 EPO 20.5Hydrocodone Bitartrate 5 HPMC 2910 2.5 Eudragit E-100 75 APAP 325 binder17.8 mannitol 192.2 microcrystalline cellulose 200 crospovidone 50magnesium stearate 40 Total 1000

Example 8 Hydrocodone Bitartrate/Acetaminophen (Celphere Core)

TABLE 20 Hydrocodone bitartrate granule composition Core Shellcomposition Component Location mg/tablet Celphere (MCC) core 117.5hydrocodone bitartrate API layer 5 HPMC 2910 API layer 2.5 EudragitE-100 film 83.4 magnesium stearate film 41.6 Total 250

TABLE 21 Hydrocodone bitartrate tablet composition Component mg/tabletCore Shell composition (above) 250 APAP 325 gelatin 12.14 mannitol 102.9microcrystalline cellulose 120 xanthan gum 30 crospovidone 150 magnesiumstearate 10 Total 1000.04

Coated spheres were prepared as in Example 7, and mixed withacetaminophen and other excipients (mannitol, microcrystallinecellulose, xanthan gum and crospovidone) and blended in a V-blender for30 minutes. Magnesium stearate was then added to lubricate the blend andthe mixture was blended for an additional 5 minutes prior to compressinginto hydrocodone tablets.

TABLE 22 Hydrocodone bitartrate granule composition Overall Tabletcomposition Component mg/tablet microcrystalline cellulose 237.5hydrocodone bitartrate 5 HPMC 2910 2.5 Eudragit E-100 83.4 APAP 325gelatin 12.14 mannitol 102.9 xanthan gum 30 crospovidone 150 magnesiumstearate 51.6 Total 1000.04

Example 9 Hydrocodone Bitartrate/Acetaminophen (Celphere Core)

TABLE 23 Hydrocodone bitartrate granule composition Core Shellcomposition Component Location mg/tablet Celphere (MCC) core 117.5hydrocodone bitartrate API layer 5 HPMC 2910 API layer 2.5 EudragitE-100 film 83.4 magnesium stearate film 41.6 Total 250

TABLE 24 Hydrocodone bitartrate tablet composition Component mg/tabletCore Shell composition (above) 250 APAP 325 gelatin 12.14 mannitol 84.9microcrystalline cellulose 120 Carbopol 30 sodium bicarbonate 18crospovidone 150 magnesium stearate 10 Total 1000.04

Coated spheres were prepared as in Example 7, and mixed withacetaminophen and other excipients (mannitol, microcrystallinecellulose, carbopol, sodium bicarbonate and crospovidone) and blended ina V-blender for 30 minutes. Magnesium stearate was then added tolubricate the blend and the mixture was blended for an additional 5minutes prior to compressing into tablets.

TABLE 25 Hydrocodone bitartrate tablet composition Overall Tabletcomposition Components mg/tablet hydrocodone bitartrate 5 HPMC 2910 2.5Eudragit E-100 83.4 APAP 325 gelatin 12.14 mannitol 84.9microcrystalline cellulose 237.5 carbopol 30 sodium bicarbonate 18crospovidone 150 magnesium stearate 51.6 Total 1000.04

Example 10 Oxycodone Hydrochloride/Acetaminophen

TABLE 26 Oxycodone bitartrate granule composition Core Shell compositionComponent Location mg/tablet HPMC K100M core 71 Compritol core 30.5Ethocel core 16.8 oxycodone hydrochloride API layer 4.5 HPMC 2910 APIlayer 2.2 Eudragit E-100 film 83.4 magnesium stearate film 41.6 Total250

TABLE 27 Oxycodone tablet composition Component mg/tablet Core Shellcomposition (above) 250 APAP 325 gelatin 12.14 lactose 84.9 carbopol 30microcrystalline cellulose 120 crospovidone 150 sodium bicarbonate 18magnesium stearate 10 Total 1000.04

Granules were prepared and coated as described in Example 1. The coatedgranules were then mixed with acetaminophen and other excipients(carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystallinecellulose) and blended in a V-blender for 30 minutes. Magnesium stearatewas then added to lubricate the blend and the mixture was blended for anadditional 5 minutes prior to compressing into oxycodone/acetaminophentablets.

TABLE 28 Oxycodone/acetaminophen tablet composition Overall Tabletcomposition Components mg/tablet HPMC K100M 71 compritol 30.5 ethocel16.8 oxycodone hydrochloride 4.5 HPMC 2910 2.2 Eudragit E-100 83.4 APAP325 gelatin 12.14 lactose 84.9 carbopol 30 microcrystalline cellulose120 crospovidone 150 sodium bicarbonate 18 magnesium stearate 51.6 Total1000

Example 11 Oxycodone Hydrochloride/Acetaminophen

TABLE 29 Oxycodone granule composition Core Shell composition ComponentLocation mg/tablet HPMC K100M core 71 compritol core 30.3 ethocel core16.7 oxycodone hydrochloride API layer 5 HPMC 2910 API layer 2.5Eudragit E-100 film 83.4 magnesium stearate film 41.6 Total 250.5

TABLE 30 Oxycodone/acetaminophen tablet composition Component mg/tabletCore Shell composition (above) 250 APAP 325 gelatin 12.14 mannitol 82.9xanthan gum 50 microcrystalline cellulose 120 crospovidone 150 magnesiumstearate 10 Total 1000.04

Granules were prepared and coated as described in Example 1. The coatedgranules were then mixed with acetaminophen and other excipients(xanthan gum, crospovidone, sodium bicarbonate, mannitol,microcrystalline cellulose) and blended in a V-blender for 30 minutes.Magnesium stearate was then added to lubricate the blend and the mixturewas blended for an additional 5 minutes prior to compressing intooxycodone/acetaminophen tablets.

TABLE 31 Oxycodone/acetaminophen tablet composition Overall Tabletcomposition Components mg/tablet HPMC K100M 71 Compritol 30.3 Ethocel16.7 oxycodone hydrochloride 5 HPMC 2910 2.5 Eudragit E-100 83.4 APAP325 Gelatin 12.14 Mannitol 82.9 xanthan gum 50 microcrystallinecellulose 120 crospovidone 150 magnesium stearate 51.6 Total 1000.54

Example 12 Oxycodone Hydrochloride/Acetaminophen

TABLE 32 Oxycodone granule composition Core Shell composition ComponentLocation mg/tablet HPMC K100M core 71 Compritol core 30.5 Ethocel core16.8 oxycodone hydrochloride API layer 4.5 HPMC 2910 API layer 2.2Eudragit E-100 film 83.4 magnesium stearate film 41.6 Total 250

TABLE 33 Oxycodone/acetaminophen tablet composition Component mg/tabletCore Shell composition (above) 250 APAP 325 Gelatin 12.14 Mannitol 52.9Carbopol 50 microcrystalline cellulose 120 Crospovidone 150 sodiumbicarbonate 30 magnesium stearate 10 Total 1000.04

Granules were prepared and coated as described in Example 1. The coatedgranules were then mixed with acetaminophen and other excipients(carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystallinecellulose) and blended in a V-blender for 30 minutes. Magnesium stearatewas then added to lubricate the blend and the mixture was blended for anadditional 5 minutes prior to compressing into oxycodone/acetaminophentablets.

TABLE 34 Oxycodone/acetaminophen tablet composition Overall Tabletcomposition Components mg/tablet HPMC K100M 71 compritol 30.5 ethocel16.8 oxycodone hydrochloride 4.5 HPMC 2910 2.2 Eudragit E-100 83.4 APAP325 gelatin 12.14 mannitol 52.9 carbopol 50 microcrystalline cellulose120 crospovidone 150 sodium bicarbonate 30 magnesium stearate 51.6 Total1000

Example 13 Hydrocodone Bitartrate/Acetaminophen

TABLE 35 Hydrocodone bitartrate granule composition Core Shellcomposition Component Location mg/tablet HPMC K100M core 51 compritolcore 21.9 ethocel core 12 hydrocodone bitartrate API layer 10 HPMC 2910API layer 5 Eudragit E-100 film 66.7 magnesium stearate film 33.3 Total199.9

TABLE 36 Hydrocodone Bitartrate/APAP tablet composition Component mg/TABCore Shell composition (above) 200 APAP 325 gelatin 12.14 mannitol 74.86carbopol 80 microcrystalline cellulose 100 crospovidone 150 sodiumbicarbonate 48 magnesium stearate 10 Total 1000

Granules were prepared and coated as described in Example 1. The coatedgranules were then mixed with acetaminophen and other excipients(carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystallinecellulose) and blended in a V-blender for 30 minutes. Magnesium stearatewas then added to lubricate the blend and the mixture was blended for anadditional 5 minutes prior to compressing into hydrocodone/acetaminophentablets.

TABLE 37 Hydrocodone Bitartrate/APAP tablet composition Overall Tabletcomposition Components mg/tablet HPMC K100M 51 Compritol 21.9 Ethocel 12hydrocodone bitartrate 10 HPMC 2910 5 Eudragit E-100 66.7 APAP 325gelatin 12.14 mannitol 74.86 carbopol 80 microcrystalline cellulose 100crospovidone 150 sodium bicarbonate 48 magnesium stearate 43.3 Total999.9

Example 14 Hydrocodone Bitartrate/Acetaminophen

TABLE 38 Hydrocodone Bitartrate granule composition Core Shellcomposition Component Location mg/tablet HPMC K100M core 42 compritolcore 18.1 ethocel core 9.9 hydrocodone bitartrate API layer 10 HPMC 2910API layer 5 Eudragit E-100 film 56.8 magnesium stearate film 28.4 Total170.2

TABLE 39 Hydrocodone/APAP tablet composition Component mg/tablet CoreShell composition (above) 170 APAP 325 gelatin 12.14 mannitol 24.905carbopol 49.98 microcrystalline cellulose 102 crospovidone 127.5 sodiumbicarbonate 30.005 magnesium stearate 8.5 Total 850.03

Granules were prepared and coated as described in Example 1. The coatedgranules were then mixed with acetaminophen and other excipients(carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystallinecellulose) and blended in a V-blender for 30 minutes. Magnesium stearatewas then added to lubricate the blend and the mixture was blended for anadditional 5 minutes prior to compressing into hydrocodone/acetaminophentablets.

TABLE 40 Hydrocodone/APAP tablet composition Overall Tablet compositionComponents mg/tablet HPMC K100M 42 compritol 18.1 ethocel 9.9hydrocodone bitartrate 10 HPMC 2910 5 Eudragit E-100 56.8 APAP 325gelatin 12.14 mannitol 24.905 carbopol 49.98 microcrystalline cellulose102 crospovidone 127.5 sodium bicarbonate 30.005 magnesium stearate 36.9Total 850.23

Example 15 Hydrocodone Bitartrate/Acetaminophen

TABLE 41 Hydrocodone granule composition Core Shell compositionComponent Location mg/tablet HPMC K100M core 51 compritol core 21.9ethocel core 12 hydrocodone bitartrate API layer 10 HPMC 2910 API layer5 Eudragit E-100 film 66.7 magnesium stearate film 33.3 Total 199.9

TABLE 42 Hydrocodone/APAP tablet composition Component mg/tablet CoreShell composition (above) 200 APAP 325 gelatin 12.14 mannitol 134.9carbopol 30 microcrystalline cellulose 120 crospovidone 150 sodiumbicarbonate 18 magnesium stearate 10 Total 1000.04

Granules were prepared and coated as described in Example 1. The coatedgranules were then mixed with acetaminophen and other excipients(carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystallinecellulose) and blended in a V-blender for 30 minutes. Magnesium stearatewas then added to lubricate the blend and the mixture was blended for anadditional 5 minutes prior to compressing into hydrocodone/acetaminophentablets.

TABLE 43 Hydrocodone/APAP tablet composition Overall Tablet compositionComponent mg/tablet HPMC K100M 51 compritol 21.9 ethocel 12 hydrocodonebitartrate 10 HPMC 2910 5 Eudragit E-100 66.7 APAP 325 gelatin 12.14mannitol 134.9 carbopol 30 microcrystalline cellulose 120 crospovidone150 sodium bicarbonate 18 magnesium stearate 43.3 Total 999.94

Example 16 Hydrocodone Bitartrate/Acetaminophen

TABLE 44 Hydrocodone granule composition Core Shell compositionComponent Location mg/tablet HPMC K100M core 51 compritol core 21.9ethocel core 12 hydrocodone bitartrate API layer 10 HPMC 2910 API layer5 Eudragit E-100 film 66.7 magnesium stearate film 33.3 Total 199.9

TABLE 45 Hydrocodone/APAP tablet composition Component mg/tablet CoreShell composition (above) 200 APAP 325 gelatin 12.14 mannitol 102.9carbopol 50 microcrystalline cellulose 120 Crospovidone 150 sodiumbicarbonate 30 magnesium stearate 10 Total 1000.04

Granules were prepared and coated as described in Example 1. The coatedgranules were then mixed with acetaminophen and other excipients(carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystallinecellulose) and blended in a V-blender for 30 minutes. Magnesium stearatewas then added to lubricate the blend and the mixture was blended for anadditional 5 minutes prior to compressing into hydrocodone/acetaminophentablets.

TABLE 46 Hydrocodone/APAP tablet composition Overall Tablet compositionComponents mg/tablet HPMC K100M 51 Compritol 21.9 Ethocel 12 hydrocodonebitartrate 10 HPMC 2910 5 Eudragit E-100 66.7 APAP 325 gelatin 12.14mannitol 102.9 carbopol 50 microcrystalline cellulose 120 crospovidone150 sodium bicarbonate 30 magnesium stearate 43.3 Total 999.94

Example 17 Hydrocodone Bitartrate/Acetaminophen

TABLE 47 Hydrocodone/APAP tablet composition Components (mg/tab) 5/325mg 7.5/325 mg 10/325 mg Hypromellose K100M PH 25.5 38.3 51.1 Compritol888 ATO 11 16.4 21.9 ethylcellulose 6 9 12 hydrocodone bitartrate 5 7.510 Hypromellose 2910 2.5 3.8 5 Eudragit E-100 33.4 50 66.7 paracetamolDc272n** 342.11 342.11 342.11 mannitol Ez 29.89 38.81 37.29 carbopol 71g50 50 50 microcrystalline cellulose 96 108 130 crospovidone 144 171 200sodium bicarbonate #1 30 30 30 Fd&C Blue #2 Ht Aluminum NA 0.54 NA LakeIron Oxide Yellow 510p NA 0.54 NA Iron Oxide Red 212p NA NA 0.6magnesium stearate non-bovine 24.6 34 43.3 alcohol SDA-3A,anhydrous * * * * purified water * * * * Total Tablet Weight 800 9001000 * Removed during Processing

Granules were prepared and coated as described in Example 1. The coatedgranules were then mixed with Paracetamol and other excipients(carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystallinecellulose and coloring agents) and blended in a V-blender for 30minutes. Magnesium stearate was then added to lubricate the blend andthe mixture was blended for an additional 5 minutes prior to compressinginto hydrocodone/acetaminophen tablets.

TABLE 48 Hydrocodone granule composition 5/325 mg 7.5/325 10/325 mg Dosemg Dose Dose % % % Granulation Hypromellose 3.19 4.26 5.11 Compritol 888ATO 1.37 1.83 2.19 ethylcellulose 0.75 1 1.2 alcohol SDA-3A,anhydrous * * * purified water * * * TOTAL 5.31 7.09 8.5 Layeringhydrocodone bitartrate 0.63 0.83 1 polymer granules (EC, HPMC and 5.317.09 8.5 Compritol) Hypromellose 2910 0.31 0.42 0.5 purified water * * *TOTAL 6.25 8.34 10 Coating hydrocodone layered 6.25 8.34 10 granules,10% Eudragit E-100 4.17 5.56 6.67 magnesium stearate 2.08 2.77 3.33alcohol, SDA-3A, anhydrous * * * TOTAL 12.5 16.67 20 * Removed duringProcessing

Example 18 Armodafinil

TABLE 49 Armodafinil tablet composition Armodafinil: Components (mg/tab)50 mg 150 mg 200 mg hypromellose 64.26 36 48 Compritol 888 ATO 17.85 1014 ethylcellulose 10.71 10 14 armodafinil 50 150 200 Eudragit E-100 2130 40 Mannitol Ez 17 25 25 Carbopol 71g 50 50 50 microcrystallinecellulose 100 125 125 crospovidone 150 200 200 sodium bicarbonate #1 3030 30 magnesium stearate non- 71 25 32 bovine Lutrol F68 (1:5) 150 200200 sodium lauryl sulphate (3%) 23 30 40 Alcohol SDA-3A, * * *anhydrous * purified water * * * * Total Tablet Weight 754.82 921 1018 *Removed during ProcessingGranules are prepared and coated as described in Example 1. The coatedgranules are then mixed with the other excipients (carbopol,crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose)and blended in a V-blender for 30 minutes. Magnesium stearate(non-bovine) is then added to lubricate the blend and the mixture isblended for an additional 5 minutes prior to compressing intoarmodafinil tablets.

TABLE 50 Armodafinil granule compositions 50 mg Dose 150 mg Dose 200 mgDose mg/g mg/tab mg/g mg/tab mg/g mg/tab Granulation hypromellose 45064.26 175 36 175 48 armodafinil 350 49.98 725 150 725 200 Compritol 12517.85 50 10 50 14 888 ATO ethylcellulose 75 10.71 50 10 50 14 AlcoholSDA-3A, * * * * * * anhydrous purified water * * * * * * TOTAL 1000142.8 1000 206 1000 276 Coating armodafinil 820 142.84 820 207 820 276granules, 35% Eudragit E-100 120 20.90 120 30 120 40 magnesium stearate60 10.45 60 15 60 20 Alcohol, SDA-3A, * * * * * * anhydrous TOTAL 1000174.2 1000 252 1000 336 * Removed during Processing

Example 19 Phenobarbital

TABLE 51 Phenobarbital Tablet compositions Components (mg/tab) 15 mg 30mg 60 mg 100 mg hypromellose 19.3 38.6 77.2 128.52 Compritol 888 ATO 5.410.7 21.4 35.7 ethylcellulose 3.2 6.4 12.9 21.43 phenobarbital 15 30 60100 Eudragit E-100 6.3 15.5 25.1 42 Mannitol Ez 20 20 20 20.1 Carbopol71g 50 50 50 50 microcrystalline cellulose 100 100 100 100 crospovidone130 130 130 200 sodium bicarbonate #1 30 30 30 30 magnesium stearatenon-bovine 9.1 12.3 19.1 31 Lutrol F68 (1:5) 100 100 120 200 sodiumlauryl sulphate (3%) 22.8 28 35 50 Alcohol SDA-3A, anhydrous * * * * *purified water * * * * * Total Tablet Weight 511.1 571.5 700.7 1008.75 *Removed during Processing

TABLE 52 Phenobarbital granule compositions 15 mg Dose 30 mg Dose 60 mgDose 100 mg Dose mg/g mg/tab mg/g mg/tab mg/g mg/tab mg/g mg/tabGranulation Hypromellose 450 19.31 450 38.57 450 77.18 450 128.57Phenobarbital 350 15.02 350 30 350 60.03 350 100 Compritol 125 5.36 12510.71 125 21.44 125 35.71 888 ATO Ethylcellulose 75 3.22 75 6.43 7512.86 75 21.43 Alcohol SDA-3A, * * * * * * * * Anhyd. PurifiedWater * * * * * * * * TOTAL 1000 42.91 1000 85.71 1000 171.51 1000285.71 Coating Phenobarbital, 35% 820 42.89 820 85.69 820 171.46 820285.69 Eudragit E-100 120 6.28 120 12.54 120 25.09 120 41.81 MagnesiumStearate 60 3.14 60 6.27 60 12.55 60 20.90 Alcohol,SDA-3A, * * * * * * * * Anhyd. TOTAL 1000 52.3 1000 104.5 1000 209.11000 348.4 * Removed during Processing

Granules are prepared and coated as described in Example 1. The coatedgranules are then mixed with the other excipients (carbopol,crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose)and blended in a V-blender for 30 minutes. Magnesium stearate(non-bovine) is then added to lubricate the blend and the mixture isblended for an additional 5 minutes prior to compressing intophenobarbital tablets.

Example 20 Diazepam

TABLE 53 Diazepam Tablet compositions 2 mg 5 mg 10 mg Components(mg/tab) (mg/tab) (mg/tab) Hypromellose K100M PH 22.2 55.6 111.2Compritol 888 ATO 9.5 23.8 47.64 Emylcellulose N10 5.2 13.1 26.2Diazepam 2 5 10 Hypromellose 2910 1 2.5 5 Eudragit E-100 26.7 66.7 133.4mannitol Ez 70 70 70 carbopol 71g 50 50 50 microcrystalline cellulose 9595 94 crospovidone 90 95 150 sodium bicarbonate #1 30 30 30 magnesiumstearate non- 18.1 38.6 74.6 bovine Alcohol SDA-3A, * * * Anhydrous *Purified Water * * * * Total Tablet Weight 419.7 545.3 802.04 * (removedduring processing)Granules are prepared and coated as described in Example 1. The coatedgranules are then mixed with the other excipients (carbopol,crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose)and blended in a V-blender for 30 minutes. Magnesium stearate(non-bovine) is then added to lubricate the blend and the mixture isblended for an additional 5 minutes prior to compressing into Diazepamtablets.

TABLE 54 Diazepam Coated Granule compositions 2 mg Dose 5 mg Dose 2 mgDose mg/g mg/tab mg/g mg/tab mg/g mg/tab Granulation hypromellose 600.8622.23 600.86 55.58 600.86 111.16 Compritol 257.51 9.53 257.51 23.82257.51 47.64 888 ATO ethylcellulose 141.63 5.24 141.63 13.10 141.6326.20 Alcohol SDA-3A, * * * * * * anhydrous purified water * * * * * *TOTAL 1000 37 1000 92.5 1000 185 Layering diazepam 50 2 50 5 50 10polymer granules (EC, 925 37 925 92.5 925 185 HPMC and Compritol)Hypromellose 2910 25 1 25 2.5 25 5 purified water * * * * * * TOTAL 100040 1000 100 1000 200 Coated, 2.5% diazepam layered 500 40 500 100 500200 granules, 5% Eudragit E-100 333.6 26.69 333.6 66.71 333.6 133.43magnesium stearate 166.4 13.31 166.4 33.29 166.4 66.57 Alcohol,SDA-3A, * * * * * * anhydrous TOTAL 1000 80 1000 200 1000 400

Example 21 Hydrocodone (Single API)

Granules are prepared and coated as described in Example 1. The coatedgranules are then mixed with the other excipients (carbopol,crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose)and blended in a V-blender for 30 minutes. Magnesium stearate(non-bovine) is then added to lubricate the blend and the mixture isblended for an additional 5 minutes prior to compressing intohydrocodone tablets.

Example 22 Hydrocodone (Single API)—(Continued from Example 21 Above)

TABLE 55 Hydrocodone Tablet compositions 5 mg 10 mg Components (mg/tab)(mg/tab) Hypromellose K100M PH 25.5 51.1 Compritol 888 ATO 11 21.9Emylcellulose N10 6 12.04 Hydrocodone Bitartrate 5 10 Hypromellose 29102.5 5 Eudragit E-100 33.4 66.7 Mannitol Ez 70 70 Carbopol 71g 50 50Microcrystalline Cellulose 95 95 Crospovidone 100 120 Sodium Bicarbonate#1 30 30 Magnesium Stearate Non-Bovine 21.6 39.3 Alcohol SDA-3A,Anhydrous * * * Purified Water * * * Total Tablet Weight 450 571.04 *(removed during processing)

TABLE 56 Hydrocodone Coated Granule compositions 5 mg Dose 10 mg Dosemg/g mg/tab mg/g mg/tab Granulation hypromellose 600.86 25.54 600.8651.07 Compritol 888 ATO 257.51 10.94 257.51 21.89 ethylcellulose 141.636.02 141.63 12.04 Alcohol SDA-3A, anhydrous * * * * purifiedwater * * * * TOTAL 1000 42.5 1000 85 Layering hydrocodone bitartrate100 5 100 10 polymer granules (EC, HPMC and 850 42.5 850 85 Compritol)Hypromellose 2910 50 2.5 50 5 purified water * * * * TOTAL 1000 50 1000100 Coating hydrocodone bitartrate layered 500 50 500 100 granules, 10%Eudragit E-100 333.6 33.36 333.6 66.71 magnesium stearate 166.4 16.64166.4 33.29 Alcohol, SDA-3A, anhydrous * * * * TOTAL * (removed during1000 100 1000 200 processing)

Example 23 Hydrocodone Bitartrate/Acetaminophen

Coated granules were prepared according to the Example 1 above. Theprepared coated granules were then mixed with Paracetamol and otherexcipients (carbomer, crospovidone, sodium bicarbonate, mannitol,microcrystalline cellulose, colorants such as FD and C blue, red ironoxide or yellow iron oxide are premixed and blended in a bin blender for30 minutes. Magnesium stearate was then added to lubricate the blend andthe resulting mixture was blended for an additional 5 minutes prior tocompressing into hydrocodone/acetaminophen tablets.

TABLE 57 Hydrocodone/APAP Tablet compositions Component (% w/w) 5/325 mg7.5/325 mg 10/325 mg Hydrocodone coated granules 12.5 16.7 20.0Paracetamol 42.76 38.0 34.21 mannitol 3.74 4.3 3.73 carbopol 6.25 5.65.0 microcrystalline cellulose 12.0 12.0 13.0 crospovidone 18.0 19.020.0 sodium bicarbonate 3.75 3.3 3.0 FD&C Blue #2 HT Aluminum NA 0.06 NALake Iron Oxide Red 212P NA NA 0.06 Iron Oxide Yellow 510P NA 0.06 NAmagnesium stearate 1.0 1.0 1.0 Total 100 100 100

Example 24 Dissolution Study of Formulations According to Examples 3

The Dosage form (intact and crushed) prepared according to Examples 3above (10/325 mg hydrocodone bitartrate/Acetaminophen tablet) was takenup in a small volume of water and extracted to simulate the amount ofhydrocodone that was available to abusers via intravenous (IV) route.The resultant mixture was assessed for ability to draw the mixturethrough a filter material into a syringe for IV injection. Variousneedle sizes and extraction volumes were evaluated. Filtrates wereassayed by HPLC for content of hydrocodone bitartrate.

TABLE 58 Amount of hydrocodone extracted from two lots of 10/325 mghydrocodone bitartrate/Acetaminophen tablets at 100° C. and RoomTemperature (RT) Intact tablet (mg) Crushed tablet (mg) Lot # 100° C. RT100° C. RT 1 0 mg 0.09 mg 0 mg 0 mg 2 0 mg 0.07 mg 0 mg 0 mg

Example 25 Simulated Nasal Fluid Extraction Study of FormulationsAccording to Example 3

The dosage form prepared according to Example 3 above (10/325 mghydrocodone bitartrate/Acetaminophen tablets) was crushed using a pestleand mortar and placed in 10 mL of simulated nasal fluid at 37° C., withgentle agitation to simulate the amount of hydrocodone bitartrateavailable for abuse by nasal insufflation. Aliquots were removed at 10and 30 minutes for analysis of hydrocodone bitartrate by HPLC. Theamount of hydrocodone bitartrate extracted from crushed tablets forsimulated nasal insufflation is provided in the table below.

This method is for the determination of hydrocodone bitartrate releasedfrom simulated nasal fluid extractions of hydrocodone bitartrateextended-release tablets.

A. HPLC Analysis Parameters

Column GL Sciences Inertsil Phenyl-3, 4.6 mm × 50 mm, 5-μm ColumnTemperature 45° C. Detection UV at 280 nm Solvent A 0.1% HFBA in waterSolvent B MeOH Mobile Phase 70:30 Solvent A:Solvent B Injector Flush50:50 MeOH:water Flow Rate 2.0 mL/min Injection Volume 50 μL Run Time 4min Peak Response Area Diluent 0.1N HCl

B. HPLC Solution Preparation

Solvent A (0.1% HFBA in H₂O): Combine 1 mL of HFBA and 1 L of HPLC gradewater, and mix well. Solvent A is stable for 14 days. Proportionatevolumes may be prepared. Mobile Phase (70:30 Solvent A:MeOH): Combine700 mL of Solvent A and 300 mL of MeOH, and mix well. Prepared solutionsare stable for 1 month. Proportionate volumes may be prepared.Alternatively, the HPLC pump may be used to mix the mobile phase.Diluent/Medium (0.1 N HCl): Combine 25 mL of 12 N HCl and 3 L of DIwater, and mix well. 0.1N HCl is stable for 4 weeks. Proportionatevolumes may be prepared. Injector Flush (50:50 MeOH:H2O): Combine 500 mLof MeOH and 500 mL of HPLC grade water, and mix well. 50:50 MeOH:H₂O isstable for 1 month. Proportionate volumes may be prepared.

C. Simulated Nasal Fluid (SNF) Preparation

Add 8.7 g sodium chloride (NaCl) 3.0 g potassium chloride (KCl), 0.6 gcalcium chloride (CaCl₂), 4.4 g sodium phosphate dibasic (Na₂HPO₄), and1.1 g sodium phosphate monobasic (NaH2PO4) in one liter of water. Mixwell. Measure and record pH (must be between 6.0 and 7.0). Store at roomtemperature. SNF is stable for 2 weeks. Proportionate volumes may beprepared.

D. Hydrocodone Bitartrate Standard Solution

Stock Standard Solution: Dry a portion of hydrocodone bitartratestandard at 2 hours under vacuum at 105° C. per the USP. In duplicate,accurately weigh 30 mg±5 mg of hydrocodone bitartrate into separate100-mL volumetric flasks. Add approximately 50 mL of 0.1 N HCl diluent.Dissolve by sonication for approximately 10 minutes. Dilute to volumewith diluent, and mix well. These are the stock standard solutions ofapproximately 300 micrograms/mL (as anhydrous hydrocodone bitartrate)and are stable for 29 days under ambient laboratory conditions(unprotected from light). Proportionate volumes may be prepared.

Working Standard Solution: Pipette 15 mL of each stock standard solutioninto separate 50-mL volumetric flasks. Dilute to volume with 0.1 N HCldiluent, and mix well. These working standard solutions areapproximately 90 micrograms/mL (as anhydrous hydrocodone bitartrate) andare stable for 43 days under ambient laboratory conditions (unprotectedfrom light). Proportionate volumes may be prepared.

E. Simulated Nasal Insufflation Extraction Sample Preparation

1. Crush one tablet and transfer approximately 575 mg, accuratelyweighed, of the crushed material to pre-labeled 20 mL glass vial. Fordrug substance controls, weigh an appropriate mass of material andtransfer into a pre-labeled 20 mL glass vial.

2. Heat the water bath and simulated nasal fluid to 37° C.

3. Pipette 10 mL the pre-heated 37° C. simulated nasal fluid into eachvial containing crushed tablet material.

4. Cap and invert two times to wet powder. Put vial on the metal shelfinside of the water bath and shake at 100 rpm.

5. At 10 min, take the vial out of shelf.

6. Uncap and withdraw a 3-mL solution from each of the vials using amicropipette.

7. Transfer solution into a 5-mL polypropylene syringe and filter thesolution through a 25-mm diameter, 1-μm porosity glass filter into aglass test tube (16×100 mm).

8. Place vial back into water bath and continue shaking

9. At 30 min, stop the shaking, uncap and withdraw a 3-mL solution fromeach of the vials using a micropipette.

10. Transfer solution into a 5-mL polypropylene syringe and filter thesolution through a 25-mm diameter, 1-μm porosity glass filter into aglass test tube (16×100 mm).

11. Pipette 1 mL of solution from each test tube into separate 50-mLvolumetric flasks and dilute to volume with 0.1 N HCl. Mix by inverting10 times.

12. Pass and discard a 1-mL aliquot of the sample solution through a25-mm diameter, 1-μm porosity, glass syringe filter prior to collectionof a second aliquot into a glass HPLC vial and cap.

13. Inject each sample once.

TABLE 59 Simulated nasal fluid extraction of 10/325 mg hydrocodonebitartrate/Acetaminophen tablets Amount extracted at Amount extracted at10 minutes from crushed 30 minutes from crushed tablets containingtablets containing 10/325 mg hydrocodone 10/325 mg hydrocodone Lotbitartrate/acetaminophen bitartrate/acetaminophen 1 14% 45% 2 60% 66%

Example 26(a) Assessment of Abuse by Multitablet Ingestion

The dosage form prepared according to Example 3 and 5 above wasevaluated for multiple tablet oral abuse resistance by stirring theselected number of tablets in 300 mL of 0.1N HCl. Dissolution wasperformed using USP Apparatus II at 50 rpm and 37° C. One to twelvetablets were added to the vessel simultaneously and aliquots wereremoved after 5, 10, 15, 30, 60, 120, 240 and 360 minutes of agitationand analyzed for hydrocodone bitartrate (FIG. 4) and APAP (FIG. 5) byHPLC. The results were plotted against time and appear in FIGS. 4 and 5.

Example 26(b) Assessment of Abuse by Multitablet Ingestion

The dosage form prepared according to Example 17 above was evaluated formultiple tablet oral abuse resistance by stirring the selected number oftablets in 300 mL of 0.1N HCl. Dissolution was performed using USPApparatus II at 50 rpm and 37° C. One to twelve tablets were added tothe vessel simultaneously and aliquots were removed after 5, 10, 15, 30,60, 120, 240 and 360 minutes of agitation and analyzed for hydrocodonebitartrate (FIG. 6) and APAP (FIG. 7) by HPLC. The results were plottedagainst time and appear in FIGS. 6 and 7.

Example 26(c) Assessment of Abuse by Multitablet Ingestion

The dosage form prepared according to Example 17 above was evaluated formultiple tablet oral abuse resistance by stirring the selected number oftablets in 300 mL of 0.1N HCl. Dissolution was performed using USPApparatus II at 50 rpm and 37° C. One to twelve tablets were added tothe vessel simultaneously and aliquots were removed after 5, 10, 15, 30,60, 120, 240 and 360 minutes of agitation and analyzed for hydrocodonebitartrate and APAP by HPLC. The results were plotted against time andappear in FIG. 8 (hydrocodone bitartrate) and FIG. 9 (APAP).

Example 27 Coated Esketamine Granules

Coated esketamine granules are prepared as per the process described inExample 1 with slight variation from Example 1 in components asillustrated below.

TABLE 60 Esketamine hydrochloride granule compositions % w/w Granulationhypromellose 60 glyceryl behenate 26 ethylcellulose 14 TOTAL 100Layering Esketamine hydrochloride 5 Polymer granules (EC, HPMC and 92.5Compritol) Hypromellose 2910 2.5 TOTAL 100 Coating esketamine layeredgranules 50 Eudragit E-100 33 magnesium stearate 17 TOTAL 100

Example 28 Esketamine HCl Tablets

The coated granules prepared per Example 27 above are subsequently mixedwith other components (carbomer, crospovidone, sodium bicarbonate,mannitol, microcrystalline cellulose) and blended in a V-blender for 30minutes. Magnesium stearate is added to lubricate the blend and theresulting mixture was blended for additional 5 minutes prior tocompressing into tablets.

TABLE 61 Esketamine hydrochloride tablet compositions Components mg/tab1 mg 2 mg 5 mg 10 mg hypromellose 11.1 22.2 55.6 111.2 glyceryl behenate4.8 9.5 23.8 47.64 ethylcellulose 2.6 5.2 13.1 26.2 Esketaminehydrochloride 1 2 5 10 Hypromellose 2910 0.5 1 2.5 5 Eudragit E-100 13.326.7 66.7 133.4 mannitol 70 70 70 70 carbopol 50 50 50 50microcrystalline cellulose 94 95 95 94 crospovidone 90 90 95 150 sodiumbicarbonate 30 30 30 30 magnesium stearate 11 18 38.6 74.6 Total TabletWeight 378.3 419.6 545.3 802.04

Example 29 Coated Esketamine Granules

Coated esketamine granules are prepared as per the process described inExample 1 with slight variation from Example 1 in components asillustrated in the Table below.

TABLE 62 Esketamine hydrochloride coated granule compositions % w/wGranulation hypromellose 60 glyceryl behenate 26 ethylcellulose 14 TOTAL100 Layering esketamine hydrochloride 10 polymer granules (EC, HPMC and85 Compritol) hypromellose 2910 5 TOTAL 100 Coating esketamine layeredgranules 50 Eudragit E-100 33 magnesium stearate 17 TOTAL 100

Example 30 Esketamine HCl Tablets

Coated granules prepared per Example 29 above are subsequently mixedwith other components (carbomer, crospovidone, sodium bicarbonate,mannitol, microcrystalline cellulose) and blended in a V-blender for 30minutes. Magnesium stearate is added to lubricate the blend and theresulting mixture was blended for additional 5 minutes prior tocompressing into tablets.

TABLE 63 Esketamine hydrochloride tablet composition Components (mg/tab)14 mg Hypromellose 71.5 Glyceryl behenate 30.6 Ethylcellulose 16.9Esketamine hydrochloride 14 Hypromellose 2910 7 Eudragit E-100 93.4Mannitol 70 Carbopol 50 Microcrystalline cellulose 130 Crospovidone 150Sodium bicarbonate 30 Magnesium stearate 55 Total Tablet Weight 718.4

Example 31 Coated Esketamine Granules

Esketamine granules are manufactured using a process similar to thatdescribed in Example 1 above with some modification to the process. Theactive ingredient instead of being layered on the granules resides inthe core where it is granulated with other excipients as per the Tablebelow, and is subsequently coated with Eudragit E-100. Granules aremanufactured in a high shear granulator where hypromellose, Esketaminehydrochloride and glyceryl behenate are dry mixed for 3 minutes. Then a10% hydroalcoholic solution of ethylcellulose is slowly added whilemaintaining the granulator impeller and chopper speed at pre-selectedvalues that provide enough shear for granule formation and growth.Solution addition is continued until the entire amount of ethylcelluloseis added. The granules are then wet milled using a size reduction mill(Granumill) and subsequently loaded into fluid bed for drying.

Esketamine hydrochloride granules are then coated in a bottom sprayfluid bed coater with 25% alcoholic suspension of Eudragit E-100copolymer and magnesium stearate (2:1). The coated granules aresubsequently used in blending and compression process.

TABLE 64 Esketamine hydrochloride granule composition % w/w GranulationEsketamine hydrochloride 35 hypromellose 45 glyceryl behenate 12.5ethylcellulose 7.5 Total 100 Coating esketamine granules 82 EudragitE-100 12 magnesium stearate 6 TOTAL 100

Example 32 Esketamine HCl Tablets

Coated granules prepared per Example 31 above are subsequently mixedwith other components (carbomer, crospovidone, sodium bicarbonate,mannitol, microcrystalline cellulose) and blended in a V-blender for 30minutes. Magnesium stearate is added to lubricate the blend and theresulting mixture was blended for additional 5 minutes prior tocompressing into tablets.

TABLE 65 Esketamine hydrochloride tablet composition Components(mg/tablet) 28 mg 56 mg 84 mg hypromellose 36 72 108 gyceryl behenate 1020 30 ethylcellulose 6 12 18 esketamine hydrochloride 28 56 84 EudragitE-100 11.7 23.4 35.1 mannitol 17 17 20.1 carbopol 50 50 50microcrystalline cellulose 100 100 100 crospovidone 150 150 150 sodiumbicarbonate 30 30 30 magnesium stearate 12 20 30 Total Tablet Weight450.7 550.4 655.2

Example 33 Coated Esketamine Granules

Esketamine granules are manufactured using a process similar to thatdescribed in Example 1 and Example 32 above with some modification tothe process. The active ingredient, is granulated with other excipientsper the table below, and is subsequently coated with Eudragit E-100.

Granules containing Esketamine hydrochloride are manufactured in a highshear granulator where hypromellose, esketamine hydrochloride andglyceryl behenate are dry mixed for 3 minutes. Then a 10% hydroalcoholicsolution of ethylcellulose is slowly added while maintaining thegranulator impeller and chopper speed at pre-selected values thatprovide enough shear for granule formation and growth. Solution additionis continued until the entire amount of ethylcellulose is added. Thegranules are then wet milled using a size reduction mill (Granumill) andthen loaded into fluid bed for drying.

The granules are then coated in a bottom spray fluid bed coater with 25%alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate(2:1). The resulting coated granules are subsequently used for blendingand compression process.

TABLE 66 Esketamine hydrochloride granule composition % w/w Granulationesketamine hydrochloride 72.5 hypromellose 17.5 glyceryl behenate 5ethylcellulose 5 TOTAL 100 Coating esketamine granules 82 Eudragit E-10012 magnesium stearate 6 Total 100

Example 34 Esketamine HCl Tablets

The coated granules prepared per Example 33 above are subsequently mixedwith other components (carbomer, crospovidone, sodium bicarbonate,mannitol, microcrystalline cellulose), and blended in a V-blender for 30minutes. Magnesium stearate is added to lubricate the blend and blendedfor additional 5 minutes prior to compressing into tablets.

TABLE 67 Esketamine hydrochloride tablet compositions Components(mg/tab) 200 mg 300 mg 400 mg Hypromellose 48 72 96.4 Glyceryl behenate14 21 27.6 Ethylcellulose 14 21 27.6 Esketamine hydrochloride 200 300400 Eudragit E-100 40 61 81 Mannitol 25 25 25 Carbopol 75 75 75Microcrystalline cellulose 125 125 125 Crospovidone 300 300 300 Sodiumbicarbonate 45 45 45 Magnesium stearate 140 150 160 Total Tablet Weight1026 1195 1362.6

Example 35 Coated Zolpidem Granules

Coated Zolpidem tartrate granules are prepared as per the processdescribed in Example 1 as per the composition illustrated in the Tablebelow.

TABLE 68 Zolpidem tartrate granule compositions % w/w Granulationhypromellose 60 glyceryl behenate 26 ethylcellulose 14 TOTAL 100Layering Zolpidem tartrate 10 polymer granules (EC, HPMC and 85Compritol) Hypromellose 2910 5 TOTAL 100 Coating Zolpidem layeredgranules 50 Eudragit E-100 33 magnesium stearate 17 TOTAL 100

Example 36 Zolpidem Tartrate Tablets

Coated zolpidem granules are prepared as per the process described inExample 35 above. The coated granules are mixed with other components(carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystallinecellulose and blended in a V-blender for 30 minutes. Magnesium stearateis added to lubricate the blend and blended for additional 5 minutesprior to compressing into tablets.

TABLE 69 Zolpidem tartrate tablet compositions Components (mg/tab) 5 mg10 mg hypromellose 25.5 51.1 glyceryl behenate 11 21.9 ethylcellulose 612 zolpidem tartrate 5 10 Hypromellose 2910 2.5 5 Eudragit E-100 33.466.7 mannitol 70 70 carbopol 50 50 microcrystalline cellulose 95 94crospovidone 100 100 sodium bicarbonate 30 30 magnesium stearate 21.639.3 Total Tablet Weight 450 550

Example 37 Coated Quetiapine Granules

Quetiapine granules are manufactured using a process similar to thatdescribed in Example 1 above with some modification to the process. TheQuetiapine fumarate, instead of being layered on the granules, residesin the core where it granulated along with other excipients per Table 70(Granulation) and is subsequently coated with Eudragit E-100 andmagnesium stearate.

Granules are manufactured in a high shear granulator where hypromellose,Quetiapine fumarate, a portion of the Lutrol, sodium lauryl sulphate andglyceryl behenate are dry mixed for 3 minutes. Then a 10% hydroalcoholicsolution of ethylcellulose is slowly added while maintaining thegranulator impeller and chopper speed at pre-selected values thatprovide enough shear for granule formation and growth. Solution additionis continued until the entire amount of ethylcellulose is added. Thegranules are then wet milled using a size reduction mill (Granumill) andthen loaded into fluid bed for drying.

The quetiapine fumarate granules are then coated in a bottom spray fluidbed coater with alcoholic suspension of Eudragit E-100 copolymer andmagnesium stearate. The resulting coated granules are then used inblending and compression process.

TABLE 70 Quetiapine fumarate coated granule composition % w/wGranulation Quetiapine fumarate 23.7 Hypromellose 37.6 Glyceryl behenate13.4 Ethylcellulose 8.1 Sodium lauryl sulphate 9.1 Lutrol 8.1 TOTAL 100Coating Quetiapine granules 62.5 Eudragit E-100 25 Magnesium stearate12.5 TOTAL 100

Example 38 Quetiapine Fumarate Tablets

The coated granules prepared per Example 37 above are subsequently mixedwith other components (carbomer, crospovidone, remaining portion ofLutrol, sodium bicarbonate, mannitol, microcrystalline cellulose), andblended in a V-blender for 30 minutes. Magnesium stearate is added tolubricate the blend and blended for additional 5 minutes prior tocompressing into tablets.

TABLE 71 Quetiapine fumarate tablet compositions 25 mg 50 mg 100 mg (mg/(mg/ (mg/ Components (mg/tablet) tablet) tablet) tablet) hypromellose 1632 63 glyceryl behenate 9 18 36 ethylcellulose 5 11 22 quetiapinefumarate 25 50 100 Eudragit E-100 27 53 107 mannitol 17 17 20.1 carbopol50 50 50 microcrystalline cellulose 100 100 100 crospovidone 150 150 200sodium bicarbonate 30 30 30 magnesium stearate 18 31 63 Lutrol 45 51 62sodium lauryl sulphate 6 12 24 Total Tablet Weight 498 605 877.1

Example 39 Coated Quetiapine Granules

Quetiapine granules are manufactured using a process similar to thatdescribed in Example 1 and with some modification to the process. TheQuetiapine fumarate, instead of being layered on the granules, residesin the core where it is granulated along with other excipients per Table72 and is subsequently coated with Eudragit E-100.

Granules are manufactured in a high shear granulator where hypromellose,Quetiapine fumarate, sodium lauryl sulphate, portion of Lutrol andglyceryl behenate are dry mixed for 3 minutes. Then a 10% hydroalcoholicsolution of ethylcellulose is slowly added while maintaining thegranulator impeller and chopper speed at pre-selected values thatprovide enough shear for granule formation and growth. Solution additionis continued until the entire amount of ethylcellulose is added. Thegranules are then wet milled using a size reduction mill (Granumill) andthen loaded into fluid bed for drying.

Quetiapine Fumarate granules are then coated in a bottom spray fluid bedcoater with alcoholic suspension of Eudragit E-100 copolymer andmagnesium stearate. The resultant coated granules are subsequently usedfor blending and compression process.

TABLE 72 Quetiapine fumarate granule compositions % w/w GranulationQuetiapine fumarate 14.3 hypromellose 59.2 glyceryl behenate 4.1ethylcellulose 4.1 sodium lauryl sulphate 10.1 Lutrol 8.2 TOTAL 100Coating Quetiapine granules 82 Eudragit E-100 12 magnesium stearate 6TOTAL 100

Example 40 Quetiapine Fumarate Tablets

The coated granules prepared as per Example 39 above are subsequentlymixed with other components (carbomer, crospovidone, sodium bicarbonate,mannitol, microcrystalline cellulose, and remaining portion of Lutrol)and blended in a V-blender for 30 minutes. Magnesium stearate is addedto lubricate the blend and blended for additional 5 minutes prior tocompressing into tablets.

TABLE 73 Quetiapine fumarate tablet compositions Components (mg/tab) 200mg 300 mg 400 mg hypromellose 48 72.5 97 glyceryl behenate 14 20.8 28ethylcellulose 14 20.8 28 quetiapine fumarate 200 300 400 Eudragit E-10040 74 99 mannitol 25 25 25 carbopol 50 65 65 microcrystalline cellulose125 125 125 crospovidone 200 275 275 sodium bicarbonate 45 45 45magnesium stearate 36 48 64 Lutrol 78 91.6 105 sodium lauryl sulphate 3451.2 69 Total Tablet Weight 909 1213.9 1425

Example 41 Coated Hydromorphone Granules

Coated hydromorphone granules are prepared as per the process describedin Example 1 with slight variation from Example 1 in components asillustrated below.

TABLE 74 Hydromorphone hydrochloride granule composition % w/wGranulation hypromellose 60 glyceryl behenate 26 ethylcellulose 14 TOTAL100 Layering hydromorphone hydrochloride 5 polymer granules (EC, HPMCand 92.5 Compritol) Hypromellose 2910 2.5 TOTAL 100 Coatinghydromorphone layered 50 granules Eudragit E-100 33 magnesium stearate17 TOTAL 100

Example 42 Hydromorphone Hydrochloride Tablets

Coated hydromorphone granules are prepared as per the process describedin Example 1 and Example 41 above. The coated granules are subsequentlymixed with other components (carbomer, crospovidone, sodium bicarbonate,mannitol, microcrystalline cellulose), and blended in a V-blender for 30minutes. Magnesium stearate is added to lubricate the blend and blendedfor additional 5 minutes prior to compressing into tablets.

TABLE 75 Hydromorphone hydrochloride tablet compositions Components(mg/tablet) 2 mg 4 mg 8 mg hypromellose 22.2 44.4 88.9 glyceryl behenate9.5 19.1 38.1 ethylcellulose 5.2 10.5 21 hydromorphone hydrochloride 2 48 Hypromellose 2910 1 2 4 Eudragit E-100 26.7 53.4 106.7 mannitol 70 7070 carbopol 50 50 50 microcrystalline cellulose 95 95 94 crospovidone 9095 150 sodium bicarbonate 30 30 30 magnesium stearate 18.1 58.3 60.4Total Tablet Weight 419.7 531.7 721.1

Example 43 Coated Methamphetamine Granules

Coated methamphetamine granules are prepared according to the processdescribed in Example 1.

TABLE 76 Methamphetamine hydrochloride granule composition % w/wGranulation hypromellose 60 glyceryl behenate 26 ethylcellulose 14 TOTAL100 Layering methamphetamine hydrochloride 5 polymer granules (EC, HPMCand 92.5 Compritol) Hypromellose 2910 2.5 TOTAL 100 Coatingmethamphetamine layered 50 granules Eudragit E-100 33 magnesium stearate17 TOTAL 100

Example 44 Methamphetamine Hydrochloride Tablets

Coated methamphetamine granules are prepared as per the processdescribed in Example 1 and Example 43 above. The coated granules aresubsequently mixed with other components (carbomer, crospovidone, sodiumbicarbonate, mannitol, microcrystalline cellulose), and blended in aV-blender for 30 minutes. Magnesium stearate is added to lubricate theblend and blended for additional 5 minutes prior to compressing intotablets.

TABLE 77 Methamphetamine hydrochloride tablet composition Components(mg/tablet) 5 mg hypromellose 55.6 glyceryl behenate 23.8 ethylcellulose13.1 methamphetamine hydrochloride 5 Hypromellose 2910 2.5 EudragitE-100 66.7 mannitol 70 carbopol 50 microcrystalline cellulose 95crospovidone 100 sodium bicarbonate 30 magnesium stearate 39 TotalTablet Weight 550.7

Example 45 Coated Oxymorphone Granules

Coated oxymorphone granules are prepared as per the process described inExample 1.

TABLE 78 Oxymorphone hydrochloride granule composition % w/w Granulationhypromellose 60 glyceryl behenate 26 ethylcellulose 14 TOTAL 100Layering oxymorphone hydrochloride 10 polymer granules (EC, HPMC and 85Compritol) Hypromellose 2910 5 TOTAL 100 Coating oxymorphone layered 50granules Eudragit E-100 33 magnesium stearate 17 TOTAL 100

Example 46 Oxymorphone Hydrochloride Tablets

Coated oxymorphone granules are prepared as per the process described inExample 1 above. The coated granules are subsequently mixed with othercomponents (carbomer, crospovidone, sodium bicarbonate, mannitol,microcrystalline cellulose), and blended in a V-blender for 30 minutes.Magnesium stearate is added to lubricate the blend and blended foradditional 5 minutes prior to compressing into tablets.

TABLE 79 Oxymorphone hydrochloride tablet compositions Components(mg/tablet) 5 mg 10 mg hypromellose 25.5 51.1 glyceryl behenate 11 21.9ethylcellulose 6 12 oxymorphone hydrochloride 5 10 Hypromellose 2910 2.55 Eudragit E-100 33.4 66.7 mannitol 70 70 carbopol 45 45microcrystalline cellulose 95 94 crospovidone 100 100 sodium bicarbonate27 27 magnesium stearate 21.6 39.3 Total Tablet Weight 442 542

Example 47 Coated Oxycodone Granules

Coated oxycodone granules are prepared as per the process described inExample 1.

TABLE 80 Oxycodone hydrochloride granule composition % w/w Granulationhypromellose 60 glyceryl behenate 26 ethylcellulose 14 TOTAL 100Layering oxycodone hydrochloride 10 polymer granules (EC, HPMC and 85Compritol) Hypromellose 2910 5 TOTAL 100 Coating oxycodone layeredgranules 50 Eudragit E-100 33 magnesium stearate 17 TOTAL 100

Example 48 Oxycodone Hydrochloride Tablets

Coated oxycodone granules are prepared as per the process described inExample 1 and Example 47 above. The coated granules are subsequentlymixed with other components (carbomer, crospovidone, sodium bicarbonate,mannitol, microcrystalline cellulose), and blended in a V-blender for 30minutes. Magnesium stearate is added to lubricate the blend and blendedfor additional 5 minutes prior to compressing into tablets.

TABLE 81 Oxycodone hydrochloride tablet compositions Components(mg/tablet) 5 mg 15 mg 30 mg hypromellose 25.5 76.6 153.3 glycerylbehenate 11 32.8 65.7 ethylcellulose 6 18.1 36.1 oxycodone hydrochloride5 15 30 Hypromellose 2910 2.5 7.5 15 Eudragit E-100 33.4 100.1 200.1mannitol 70 37.29 70 carbopol 45 50 50 microcrystalline cellulose 95 13094 crospovidone 100 150 200 sodium bicarbonate 27 30 30 magnesiumstearate 21.6 57 110 Total Tablet Weight 442 704.39 1054.2

Example 49 Coated Morphine Sulphate Granules

Coated morphine granules are prepared as per the process described inExample 1.

TABLE 82 Morphine Sulfate tablet compositions % w/w Granulationhypromellose 60 glyceryl behenate 26 ethylcellulose 14 TOTAL 100Layering morphine sulphate 10 polymer granules (EC, HPMC and 85Compritol) Hypromellose 2910 5 TOTAL 100 Coating morphine layeredgranules 50 Eudragit E-100 33 magnesium stearate 17 TOTAL 100

Example 50 Morphine Sulphate Tablets

Coated morphine granules are prepared as per the process described inExample 1 and Example 49 above. The coated granules are subsequentlymixed with other components (carbomer, crospovidone, sodium bicarbonate,mannitol, microcrystalline cellulose), and blended in a V-blender for 30minutes. Magnesium stearate is added to lubricate the blend and blendedfor additional 5 minutes prior to compressing into tablets.

TABLE 83 Morphine sulphate tablet compositions Components (mg/tablet) 6mg 15 mg 30 mg hypromellose 30.6 76.6 153.3 glyceryl behenate 13.1 32.865.7 ethylcellulose 7.2 18.1 36.1 morphine sulphate 6 15 30 Hypromellose2910 3 7.5 15 Eudragit E-100 40.02 100.1 200.1 mannitol 70 70 70carbopol 45 50 50 microcrystalline cellulose 95 130 94 crospovidone 100150 200 sodium bicarbonate 27 30 30 magnesium stearate 24.5 57 110 TotalTablet Weight 461.42 737.1 1054.2

Example 51 Coated Mixed Amphetamine Salts Granules

Coated granules containing mixed amphetamine salts (dextroamphetaminesaccharate, amphetamine aspartate, dextroamphetamine sulfate,amphetamine sulfate) are prepared as per the process described inExample 1.

TABLE 84 Mixed amphetamine salt granule formulation % w/w Granulationhypromellose 60 glyceryl behenate 26 ethylcellulose 14 TOTAL 100Layering Mixed amphetamine salts* 10 polymer granules (EC, HPMC and 85Compritol) Hypromellose 2910 5 TOTAL 100 Coating mixed amphetamine saltlayered 50 granules Eudragit E-100 33 magnesium stearate 17 TOTAL 100*Dextroamphetamine saccharate, amphetamine aspartate monohydrateequivalent, dextroamphetamine sulfate, amphetamine sulfate.

Example 52 Mixed Amphetamine Salt Tablets

Coated granules containing mixed amphetamine salts are prepared as perthe process described in Example 1 and Example 51 above. The coatedgranules are subsequently mixed with other components such as carbomer,crospovidone, sodium bicarbonate, mannitol, microcrystalline celluloseand blended in a V-blender for 30 minutes. Magnesium stearate is addedto lubricate the blend and blended for additional 5 minutes prior tocompressing into tablets.

TABLE 85 Mixed amphetamine salt tablet formulation TotalAmphetamine/Base Equivalence Components 3.13 mg 4.7 mg 6.3 mg 7.8 mg 9.4mg 12.6 mg 18.8 mg (mg/tablet) 5 mg 7.5 mg 10 mg 12.5 mg 15 mg 20 mg 30mg hypromellose 25.5 38.3 51.1 63.8 76.6 102.15 153.3 glyceryl behenate10.9 16.4 21.9 27.4 32.8 43.8 65.7 ethylcellulose 6.02 9.03 12.04 15.0518.1 24.1 36.1 Mixed amphet- 5 7.5 10 12.5 15 20 30 amine salts*Hypromellose 2910 2.5 3.75 5 6.25 7.5 10 15 Eudragit E-100 33.4 50.0466.7 83.4 100.1 133.4 200.1 mannitol 70 70 70 70 70 70 70 carbopol 45 4545 50 50 50 50 microcrystalline 95 95 95 130 130 130 150 cellulosecrospovidone 100 100 100 150 150 160 200 sodium bicarbonate 27 27 27 3030 30 30 magnesium stearate 21.5 30 38.6 48 57 75 110 Total TabletWeight 441.82 492.02 542.34 686.4 737.1 848.45 1110.2 *dextroamphetaminesaccharate, amphetamine aspartate monohydrate equivalent,dextroamphetamine sulfate, amphetamine sulfate.

Example 53 Codeine Phosphate Granules

Coated granules containing Codeine phosphate are prepared as per theprocess described in Example 1 with some modifications to thecomposition as described below.

TABLE 86 Codeine phosphate granule formulation % w/w GranulationHypromellose 60 Glyceryl behenate 26 Ethylcellulose 14 TOTAL 100Layering Codeine phosphate. 20 Polymer Granules (EC, HPMC and 70Compritol) Hypromellose 2910 10 TOTAL 100 Coating Codeine phosphatelayered 70 granules Eudragit E-100 20 Magnesium Stearate 10 TOTAL 100

Example 54 Codeine Phosphate Tablets

Coated granules containing codeine phosphate are prepared as per theprocess described in Example 1 and Example 53 above. The coated granulesare subsequently mixed with other active ingredient (paracetamol), andother components (carbomer, crospovidone, sodium bicarbonate, mannitol,colorant, microcrystalline cellulose), and blended in a V-blender for 30minutes. Magnesium stearate is added to lubricate the blend and blendedfor additional 5 minutes prior to compressing into tablets.

TABLE 87 Codeine phosphate tablet formulation Components (mg/tablet)30/300 mg 60/300 mg hypromellose 63.1 126.2 glyceryl behenate 27 54.1ethylcellulose 14.9 29.7 codeine phosphate 30 60 Hypromellose 2910 15 30Eudragit E-100 42.9 85.7 Paracetamol* 315.8 315.8 mannitol 29.4 29.4carbopol 50 50 microcrystalline cellulose 180 180 crospovidone 200 200sodium bicarbonate 30 30 Fd&c blue # 2 NA 0.6 Iron Oxide Yellow 510P 0.5NA magnesium stearate 31.5 57 Total Tablet Weight 1030.1 1248.5 *Theparacetamol grade Contains 300 mg of APAP and 15.8 mg of gelatin

Example 55 Methylphenidate Hydrochloride Granules

Coated granules containing methylphenidate hydrochloride are prepared asper the process described in Example 1.

TABLE 88 Methylphenidate hydrochloride granule formulation % w/wGranulation hypromellose 60 glyceryl behenate 26 ethylcellulose 14 TOTAL100 Layering methylphenidate hydrochloride 10 polymer granules (EC, HPMCand 85 Compritol) Hypromellose 2910 5 TOTAL 100 Coating methylphenidatehydrochloride 50 Layered Granules Eudragit E-100 33 magnesium stearate17 TOTAL 100

Example 56 Methylphenidate Hydrochloride Tablets

Coated granules containing methylphenidate hydrochloride are prepared asper the process described in Example 1 and Example 55 above. The coatedgranules are subsequently mixed with other components (carbomer,crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose),and blended in a V-blender for 30 minutes. Magnesium stearate is addedto lubricate the blend and blended for additional 5 minutes prior tocompressing into tablets.

TABLE 89 Methylphenidate hydrochloride tablet formulation Components(mg/tablet) 5 mg 20 mg hypromellose 25.5 102.15 glyceryl behenate 10.943.8 ethylcellulose 6.02 24.1 methylphenidate hydrochloride 5 20Hypromellose 2910 2.5 10 Eudragit E-100 33.4 133.4 mannitol 70 70carbopol 45 50 microcrystalline cellulose 95 150 crospovidone 100 160sodium bicarbonate 27 30 magnesium stearate 21.5 75 Total Tablet Weight441.82 868.45

Example 57 Oxycodone Hydrochloride Granules

Coated granules containing oxycodone hydrochloride were prepared andcoated as per the process described in Example 1.

TABLE 90 Oxycodone hydrochloride granule formulation % w/w GranulationHypromellose 60 Glyceryl behenate 26 Ethylcellulose 14 TOTAL 100Layering Oxycodone hydrochloride 10 Polymer granules (EC, HPMC and 85Compritol) Hypromellose 2910 5 TOTAL 100 Coating Oxycodone layeredgranules, 10% 50 Eudragit E-100 33 Magnesium stearate 17 TOTAL 100

Granules were manufactured in a high shear granulator where Hypromelloseand glyceryl behenate were dry mixed for 3 minutes. Then a 10%hydroalcoholic solution of ethylcellulose N10 was slowly added whilemaintaining the granulator impeller and chopper speed at pre-selectedvalues that provide enough shear for granule formation and growth.Solution addition was continued until the entire amount ofethylcellulose was added. The granules were then wet milled using a sizereduction mill (Granumill) and were subsequently loaded into fluid bedfor drying.

The prepared granules were then layered in a bottom spray fluid bedcoater with a 12% aqueous solution of oxycodone hydrochloride and HPMC2910 (2:1).

The oxycodone hydrochloride layered granules were then coated in abottom spray fluid bed coater with 25% alcoholic suspension of EudragitE-100 copolymer and magnesium stearate (2:1). The resulting coatedgranules were subsequently used for further blending and compressionprocess.

Example 58 Oxycodone/Acetaminophen Tablets

The coated granules prepared according to the example 57 above weremixed with another active agent, Paracetamol, and other excipients(carbomer, crospovidone, sodium bicarbonate, mannitol, FD&C blue,microcrystalline cellulose), and blended in a V-blender for 30 minutes.Magnesium stearate was then added to lubricate the blend and blended foradditional 5 minutes prior to compressing into oxycodone/APAP tablets.

TABLE 91 Oxycodone hydrochloride tablet formulation Component % w/woxycodone coated granules 20.0 Paracetamol* 33.7 mannitol 4.2 carbopol5.0 microcrystalline cellulose 13.0 crospovidone 20.0 sodium bicarbonate3.0 FD and C blue 0.06 magnesium stearate 1.0 Total 100 *Contains 95%acetaminophen and 5% gelatin

Example 59 Oxycodone/Acetaminophen Tablets

The coated granules prepared according to the example 57 above weremixed with another active agent, Paracetamol, and other excipients(carbomer, crospovidone, sodium bicarbonate, mannitol, FD&C blue,microcrystalline cellulose), and blended in a V-blender for 30 minutes.Magnesium stearate was then added to lubricate the blend and blended foradditional 5 minutes prior to compressing into oxycodone/APAP tablets.

TABLE 92 Oxycodone/acetaminophen tablet formulations Component (% w/w)5/325 mg 7.5/325 mg 10/325 mg oxycodone coated granules 12.5 16.7 20.0paracetamol* 42.8 38.0 34.2 mannitol 3.7 4.37 3.79 carbopol 6.25 5.6 5microcrystalline cellulose 12 12 13 crospovidone 18 19 20 sodiumbicarbonate 3.75 3.3 3 Iron Oxide yellow 0.06 NA NA FD&C Blue # 2 NA0.06 NA magnesium stearate 1.0 1.0 1.0 Total 100 100 100 *Contains 95%acetaminophen and 5% gelatin

Example 60 Armodafinil Granules

Armodafinil granules are manufactured using a process similar to thatdescribed in Example 1 and with some modification to the process. Theactive ingredient, Armodafinil, instead of being layered on thegranules, resides in the core where it is granulated along with otherexcipients as per Table 93, and is subsequently coated with EudragitE-100.

Granules are manufactured in a high shear granulator where hypromellose,Armodafinil, povidone and glyceryl behenate are dry mixed for 3 minutes.Then a 10% hydroalcoholic solution of ethylcellulose is slowly addedwhile maintaining the granulator impeller and chopper speed atpre-selected values that provide enough shear for granule formation andgrowth. Solution addition is continued until the entire amount ofethylcellulose is added. The granules are then wet milled using a sizereduction mill (Granumill) and subsequently loaded into fluid bed fordrying.

Armodafinil granules are then coated in a bottom spray fluid bed coaterwith alcoholic suspension of Eudragit E-100 copolymer and magnesiumstearate. The resultant coated granules are subsequently used forblending and compression process.

TABLE 93 Armodafinil granule formulations % w/w Granulation armodafinil66.99 hypromellose 16.75 glyceryl behenate 3.83 ethylcellulose 3.83povidone 8.61 TOTAL 100 Coating Armodafinil granules 70 Eudragit E-10020 magnesium stearate 10 TOTAL 100

Example 61 Armodafinil Tablets

The coated granules prepared as per Example 60 above are subsequentlymixed with other components (carbomer, crospovidone, sodium bicarbonate,mannitol, microcrystalline cellulose), and blended in a V-blender for 30minutes. Magnesium stearate is added to lubricate the blend and blendedfor additional 5 minutes prior to compressing into tablets.

TABLE 94 Armodafinil tablet formulations 50 mg 150 mg 200 mg (mg/ (mg/(mg/ Components (mg/tablet) tablet) tablet) tablet) hypromellose 12.537.5 50 glyceryl behenate 2.9 8.6 11 ethylcellulose 2.9 8.6 11armodafinil 50 150 200 Eudragit E-100 21.3 64 85 mannitol 17 25 25carbopol 50 50 50 microcrystalline cellulose 100 125 125 crospovidone150 200 200 sodium bicarbonate 30 30 30 magnesium stearate 16 40 52povidone 6.4 19.3 26 Total Tablet Weight 459 758 865

Example 62 Phenobarbital Granules

Phenobarbital granules are manufactured using a process similar to thatdescribed in Example 1 and with some modification to the process. Theactive ingredient, Phenobarbital, instead of being layered on thegranules, resides in the core where it is granulated along with otherexcipients per the Table below, and is subsequently coated with EudragitE-100.

Granules are manufactured in a high shear granulator where hypromellose,phenobarbital, povidone and glyceryl behenate are dry mixed for 3minutes. Then a 10% hydroalcoholic solution of ethylcellulose is slowlyadded while maintaining the granulator impeller and chopper speed atpre-selected values that provide enough shear for granule formation andgrowth. Solution addition is continued until the entire amount ofethylcellulose is added. The granules are then wet milled using a sizereduction mill (Granumill) and subsequently loaded into fluid bed fordrying.

The phenobarbital granules are then coated in a bottom spray fluid bedcoater with alcoholic suspension of Eudragit E-100 copolymer andmagnesium stearate. The resultant coated granules are subsequently usedfor blending and compression process.

TABLE 95 Phenobarbital granule formulations % w/w GranulationPhenobarbital 66.99 hypromellose 16.75 glyceryl behenate 3.83ethylcellulose 3.83 povidone 8.61 TOTAL 100 Layering Phenobarbitalgranules 50 Eudragit E-100 33 magnesium stearate 17 TOTAL 100

Example 63 Phenobarbital Tablets

The coated granules prepared as per Example 62 above are subsequentlymixed with other components (carbomer, crospovidone, sodium bicarbonate,mannitol, microcrystalline cellulose), and blended in a V-blender for 30minutes. Magnesium stearate is added to lubricate the blend and blendedfor additional 5 minutes prior to compressing into tablets.

TABLE 96 Phenobarbital tablet formulations 15 mg 30 mg 60 mg 100 mg (mg/(mg/ (mg/ (mg/ Components tablet) tablet) tablet) tablet) hypromellose3.8 7.5 15 25.01 glyceryl behenate 1 2 3.4 5.72 ethylcellulose 1 2 3.45.72 phenobarbital 15 30 60 100 Eudragit E-100 15 30 59 98.5 mannitol 2020 20 20 carbopol 50 50 50 50 microcrystalline cellulose 75 100 100 100crospovidone 130 130 200 200 sodium bicarbonate 30 30 30 30 magnesiumstearate 12 20 36 59 povidone 2 4 7.7 12.9 Total Tablet Weight 354.8425.5 584.5 706.85

Example 64 Diazepam Granules

Coated diazepam granules are prepared as per the process described inExample 1 with slight variation from Example 1 in components asillustrated in the Table below.

TABLE 97 Diazepam granule formulations % w/w Granulation hypromellose 60glyceryl behenate 26 ethylcellulose 14 TOTAL 100 Layering diazepam 5polymer granules (EC, HPMC and 92.5 Compritol) Hypromellose 2910 2.5TOTAL 100 Coating diazepam layered granules 50 Eudragit E-100 33magnesium stearate 17 TOTAL 100

Example 65 Diazepam Tablets

Coated diazepam granules are prepared as per the process described inExample 1 and Example 64 above. The coated granules are subsequentlymixed with other components (carbomer, crospovidone, sodium bicarbonate,mannitol, microcrystalline cellulose), and blended in a V-blender for 30minutes. Magnesium stearate is added to lubricate the blend and blendedfor additional 5 minutes prior to compressing into tablets.

TABLE 98 Diazepam tablet formulations Components (mg/tablet) 2 mg 5 mg10 mg hypromellose 22.2 55.6 111.2 glyceryl behenate 9.5 23.8 47.64ethylcellulose 5.2 13.1 26.2 diazepam 2 5 10 Hypromellose 2910 1 2.5 5Eudragit E-100 26.7 66.7 133.4 mannitol 70 70 70 carbopol 50 50 50microcrystalline cellulose 95 95 94 crospovidone 120 120 150 sodiumbicarbonate 30 30 30 magnesium stearate 18.1 38.6 74.6 Total TabletWeight 449.7 570.3 802.04

Example 66 Hydrocodone Bitartrate Granules

Coated granules containing hydrocodone bitartrate are prepared as perthe process described in Example 1.

TABLE 99 Hydrocodone bitartrate granule formulations % w/w GranulationHypromellose 60 Glyceryl behenate 26 Ethylcellulose 14 TOTAL 100Layering Hydrocodone bitartrate 10 Polymer granules (EC, HPMC and 85Compritol) Hypromellose 2910 5 TOTAL 100 Coating Hydrocodone bitartratelayered 50 granules Eudragit E-100 33 Magnesium stearate 17 TOTAL 100

Example 67 Hydrocodone Bitartrate Tablets

Coated granules containing hydrocodone bitartrate are prepared as perthe process described in Example 1 and Example 66 above. The coatedgranules are subsequently mixed with other components (carbomer,crospovidone, sodium bicarbonate, mannitol, microcrystalline celluloseand blended in a V-blender for 30 minutes. Magnesium stearate is addedto lubricate the blend and blended for additional 5 minutes prior tocompressing into tablets.

TABLE 100 Hydrocodone Tablet Formulations 5 mg 10 mg (mg/ (mg/Components tablet) tablet) hypromellose 25.5 51.1 glyceryl behenate 1121.9 ethylcellulose 6 12.04 hydrocodone bitartrate 5 10 Hypromellose2910 2.5 5 Eudragit E-100 33.4 66.7 mannitol 70 70 carbopol 50 50microcrystalline cellulose 95 95 crospovidone 100 120 sodium bicarbonate30 30 magnesium stearate 21.6 39.3 Total Tablet Weight 450 571.04

What is claimed is:
 1. An immediate release abuse deterrent dosage formcomprising: a) core-shell particles, the core-shell particlescomprising: i) a core, the core comprising at least one of: a wax, asugar sphere, a microcrystalline cellulose sphere or a gelling polymer;ii) an active pharmaceutical layer surrounding the core, the activepharmaceutical layer comprising an active pharmaceutical ingredientwhich is commonly susceptible to abuse, wherein the activepharmaceutical ingredient is selected from: a narcotic analgesic, asedative-hypnotic, a CNS stimulant, an anxiolytic, an antipsychotic, adissociative anesthetic, and a muscle relaxant; and iii) at least onefilm layer surrounding the active pharmaceutical layer, at least onefilm layer comprising a film forming polymer; and b) a matrix comprisinga disintegrant and a gelling polymer.
 2. The immediate release abusedeterrent dosage form according to claim 1, wherein the core containsless than 5 weight percent of a total amount of the activepharmaceutical ingredient in the core-shell particles.
 3. The immediaterelease abuse deterrent dosage form according to claim 1, wherein theactive pharmaceutical ingredient is a narcotic analgesic.
 4. Theimmediate release abuse deterrent dosage form according to claim 3,wherein the narcotic analgesic is an opioid.
 5. The immediate releaseabuse deterrent dosage form according to claim 4, wherein the opioid isselected from buprenorphine, codeine, dihydrocodeine, dihydromorphine,hydrocodone, hydromorphone, pseudoephedrine, morphine, oxycodone,oxymorphone, and pharmaceutically acceptable salts thereof.
 6. Theimmediate release abuse deterrent dosage form according to claim 1,wherein the active pharmaceutical ingredient is a sedative-hypnotic. 7.The immediate release abuse deterrent dosage form according to claim 6,wherein the sedative-hypnotic is selected from barbiturates,benzodiazepines, phenothiazines, and sleep medications.
 8. The immediaterelease abuse deterrent dosage form according to claim 7, wherein thesedative-hypnotic is a sleep medication selected from zolpidem,zaleplon, eszopiclone and pharmaceutically acceptable salts thereof. 9.The immediate release abuse deterrent dosage form according to claim 1,wherein the active pharmaceutical ingredient is a CNS stimulant.
 10. Theimmediate release abuse deterrent dosage form according to claim 9,wherein the CNS stimulant is selected from amphetamines andnon-amphetamine psychostimulants.
 11. The immediate release abusedeterrent dosage form according to claim 9, wherein the CNS stimulant isan amphetamine selected from dextroamphetamine, levoamphetamine,methamphetamine, pseudoephedrine, Adderall and pharmaceuticallyacceptable salts thereof.
 12. The immediate release abuse deterrentdosage form according to claim 9, wherein the CNS stimulant is anon-amphetamine psychostimulant selected from methylphenidate andpharmaceutically acceptable salts thereof, modafinil and armodafinil.13. The immediate release abuse deterrent dosage form according to claim1, wherein the active pharmaceutical ingredient is an anxiolytic. 14.The immediate release abuse deterrent dosage form according to claim 13,wherein the anxiolytic is a benzodiazepine selected from diazepam,chlordiazepoxide, estazolam, lorazepam, triazolam, alprazolam,clonazepam, flurazepam and pharmaceutically acceptable salts thereof.15. The immediate release abuse deterrent dosage form according to claim1, wherein the active pharmaceutical ingredient is an antipsychotic. 16.The immediate release abuse deterrent dosage form according to claim 15,wherein the antipsychotic is selected from phenothiazines,butyrophenones, dibenzoxazepines and atypical antipsychotic agents. 17.The immediate release abuse deterrent dosage form according to claim 15,wherein the antipsychotic is an atypical antipsychotic agent selectedfrom aripiprazole, clozapine, olanzapine, quetiapine, risperidoneziprasidone, paliperidone and remoxipride.
 18. The immediate releaseabuse deterrent dosage form according to claim 1, wherein the activepharmaceutical ingredient is a muscle relaxant.
 19. The immediaterelease abuse deterrent dosage form according to claim 18, wherein themuscle relaxant is selected from cyclobenzaprine and pharmaceuticallyacceptable salts thereof, cannabinols and cannabinoids.
 20. Theimmediate release abuse deterrent dosage form according to claim 1,wherein the active pharmaceutical ingredient is a dissociativeanesthetic.
 21. The immediate release abuse deterrent dosage formaccording to claim 20, wherein the dissociative anesthetic is selectedfrom Ketamine or Esketamine.
 22. The immediate release abuse deterrentdosage form according to claim 1, wherein the core comprises a gellingpolymer or a wax.
 23. The immediate release abuse deterrent dosage formaccording to claim 22, wherein the core further comprises a binder. 24.The immediate release abuse deterrent dosage form according to claim 23,wherein the binder is selected from: alginic acid, sodiumcarboxymethylcellulose, microcrystalline cellulose, dextrin,ethylcellulose, gelatin, starch, pregelatinized starch, polyvinylalcohol, polyethylene oxide, polyvinylpyrrolidone, polyacrylamides,polyvinyloxoazolidone, polyvinylalcohols, methylcellulose, hydroxypropylcellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose,hydroxymethyl cellulose and any combination thereof.
 25. The immediaterelease abuse deterrent dosage form according to claim 24, wherein thecore comprises a gelling polymer, a wax and a binder selected from:alginic acid, sodium carboxymethylcellulose, microcrystalline cellulose,dextrin, ethylcellulose, gelatin, starch, pregelatinized starch,polyvinyl alcohol, polyethylene oxide, polyvinylpyrrolidone,polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols,methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose andany combination thereof.
 26. The immediate release abuse deterrentdosage form according to claim 1, wherein the core comprises a gellingpolymer selected from a natural starch, a synthetic starch, a naturalcellulose, a synthetic cellulose, an acrylate, a polyalkylene oxide, apoly(acrylic acid), and combinations thereof.
 27. The immediate releaseabuse deterrent dosage form according to claim 26, wherein the gellingpolymer in the core is selected from ethylcellulose, cellulose acetate,cellulose acetate propionate, cellulose acetate butyrate, celluloseacetate phthalate, cellulose triacetate, cellulose ether, celluloseester, cellulose ester ether, cellulose, an acrylic acid and methacrylicacid copolymer, a methyl methacrylate copolymer, an ethoxyethylmethacrylate, a cyanoethyl methacrylate, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamide copolymer,poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate)copolymer, polyacrylamide, aminoalkyl methacrylate copolymer,poly(methacrylic acid anhydride), glycidyl methacrylate copolymer, agar,acacia, karaya, tragacanth, algin, guar; polyacrylamide; water-swellableindene maleic anhydride polymer, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, methyl cellulose, hydroxyethylmethyl cellulose, sodiumcarboxymethyl cellulose, a carbomer polymer, polyethylene oxide,polyvinyl alcohol and combinations thereof.
 28. The immediate releaseabuse deterrent dosage form according to claim 26, wherein the gellingpolymer in the core is selected from hydroxypropyl methyl cellulose,hydroxy methyl cellulose, methyl cellulose, hydroxyethylmethylcellulose, sodium carboxymethyl cellulose, a carbomer polymer,polyethylene oxide, polyvinyl alcohol and combinations thereof.
 29. Theimmediate release abuse deterrent dosage form according to claim 1,wherein the wherein the core comprises a wax.
 30. The immediate releaseabuse deterrent dosage form according to claim 29, wherein the waxcomprises a fatty acid ester, a fatty glyceride derivative, or a fattyalcohol.
 31. The immediate release abuse deterrent dosage form accordingto claim 30, wherein the wax is selected from glyceryl behenate,glycerol palmitostearate, a stearoyl macroglyceride, carnauba wax, beeswax, microcrystalline wax, cetyl alcohol, and a combination thereof. 32.The immediate release abuse deterrent dosage form according to claim 1,wherein the wherein the core comprises a microcrystalline cellulosesphere or a sugar sphere.
 33. The immediate release abuse deterrentdosage form according to claim 1, wherein the gelling polymer in thematrix is selected from a natural starch, a synthetic starch, a naturalcellulose, a synthetic cellulose, an acrylate, a polyalkylene oxide, andcombinations thereof.
 34. The immediate release abuse deterrent dosageform according to claim 33, wherein the gelling polymer in the matrix isselected from hydroxypropyl methyl cellulose, hydroxy methyl cellulose,methyl cellulose, hydroxyethylmethyl cellulose, sodium carboxymethylcellulose, a carbomer polymer, and combinations thereof.
 35. Theimmediate release abuse deterrent dosage form according to claim 1,wherein the disintegrant in the matrix is selected from corn starch,croscarmellose sodium, crospovidone, sodium starch glycolate, PVP, HPC,pregelatinized starch and a combination thereof.
 36. The immediaterelease abuse deterrent dosage form according to claim 35, wherein thedosage form comprises from 0.5 to 50 weight percent disintegrant basedon total weight of the dosage form.
 37. The immediate release abusedeterrent dosage form according to claim 1, wherein the at least onefilm layer surrounding the active pharmaceutical layer comprises apH-sensitive film forming polymer.
 38. The immediate release abusedeterrent dosage form according to claim 37, wherein the pH-sensitivefilm forming polymer is insoluble in water at a pH greater than 5 and issoluble in water at a pH below
 5. 39. The immediate release abusedeterrent dosage form according to claim 38, wherein the pH-sensitivefilm forming polymer is a copolymer of dimethyl aminoethyl methacrylate,butyl methacrylate, and methyl methacrylate monomers.
 40. The immediaterelease abuse deterrent dosage form according to claim 1, wherein thedosage form excludes an emetic, a nasal irritant, and an effervescent.41. The immediate release abuse deterrent dosage form according to claim4, wherein the dosage form excludes an opioid antagonist.
 42. Theimmediate release abuse deterrent dosage form according to claim 1wherein the dosage form is in a suppository, capsule, caplet, pill, gel,soft gelatin capsule, or compressed tablet form.
 43. The immediaterelease abuse deterrent dosage form according to claim 42 wherein thedosage form is in a compressed tablet form.
 44. A method of preventing,alleviating, or ameliorating a level of pain in a subject, the methodcomprising administering to the subject a dosage form as recited atclaim 3.